What changed in this filing

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Item 1. Business

2021-02-25 compared with 2020-03-05 · 129 added, 78 removed, 234 unchanged (47% of the section changed)

Caladrius Biosciences, Inc.

(“we,” “us,” "our," “Caladrius” or the “Company”) is a clinical-stage biopharmaceutical company dedicated to the development of cellular therapies designed to reverse, not manage, cardiovascular disease.

We are developing first-in-class therapy products that are based on the notion that our bodies contain finely tuned mechanisms for self-repair.

Our technology leverages and enables these mechanisms in the form of specific cells, using formulations unique to each indication.

Our leadership team collectively has decades of biopharmaceutical development experience and world-recognized scientific achievement in the field of cardiovascular disease, among other fields.

Our goal is to build a broad portfolio of novel and versatile products that address important unmet medical needs.

Our current product candidates include three developmental treatments for ischemic diseases based on our CD34+ cell therapy platform:

CLBS12, recipient of SAKIGAKE designation (a Japanese regulatory status that is similar in certain respects to "breakthrough therapy" designation granted by the U.S.

Food and Drug Administration (the "FDA") to eligible investigational treatments) and eligible for early conditional approval in Japan for the treatment of critical limb ischemia ("CLI") based on the results of an ongoing clinical trial;

CLBS16, a Phase 2 clinical trial in the U.S.

(“we,” “us,” "our," “Caladrius” or the “Company”) is a clinical-stage biopharmaceutical company dedicated to the development and commercialization of cellular therapies designed to reverse disease and/or promote the regeneration of damaged tissue.

We are developing first-in-class therapeutics based on the characteristics of naturally occurring CD34+ cells and their ability to stimulate the growth of new microvasculature.

Our technology leverages these cells to enable the body's natural repair mechanisms using formulations unique to each medical indication.

Our leadership team has decades of collective biopharmaceutical development experience.

Our goal is to develop and commercialize products that address important unmet medical needs based on a broad and versatile portfolio of candidates.

The Company’s current product candidates include:

CLBS16, the subject of both a recently completed positive Phase 2a study and a newly initiated Phase 2b (FREEDOM) study in the U.S.

for the treatment of coronary microvascular dysfunction (“CMD”);

and CLBS14, a Regenerative Medicine Advanced Therapy ("RMAT") designated therapy for which we have finalized with the FDA a protocol for a Phase 3 confirmatory trial in subjects with no-option refractory disabling angina ("NORDA").

Additional Out-licensing Opportunities

Our broad intellectual property portfolio of cell therapy assets includes notable programs available for out-licensing in order to continue their clinical development.

Our current long-term strategy is to advance our therapies through development with the ultimate objective of obtaining market authorizations and entering commercialization, either alone or with partners, and to provide treatment options to patients suffering from life-threatening medical conditions.

We believe that we are well-positioned to realize potentially meaningful value increases within our own proprietary pipeline if we are successful in advancing our product candidates to their next significant development milestones.

HONEDRA® (CLBS12), recipient of SAKIGAKE designation and eligible for early conditional approval in Japan for the treatment of critical limb ischemia (“CLI”) and Buerger’s Disease based on the results of an ongoing clinical trial;

CLBS201, designed to assess the safety and efficacy of CD34+ cell therapy as a treatment for patients with pre-dialysis chronic kidney disease (“CKD”) and OLOGO™ (CLBS14), a Regenerative Medicine Advanced Therapy (“RMAT”) designated therapy for which the Company is in discussion with the U.S.

Food and Drug Administration (the “FDA”) to finalize a Phase 3 protocol of reduced size and scope for a confirmatory trial in subjects with no-option refractory disabling angina ( “NORDA”).

Corporate Information

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All trademarks, service marks and traded names included herein are the property of their respective owners.

Ischemic Repair (CD34 Cell Technology)

The CD34+ cell was discovered as a result of the deliberate search for a stem cell capable of stimulating the development and/or repair of blood vessels.

All tissues in the body maintain their function by replacing cells over time.

In addition to the maintenance function, the body must also be capable of building new blood vessels after injury.

A CD34+ cell is a stem cell that has the ability to stimulate new blood vessel formation at the level of the microvasculature.

No other native cell discovered to date has demonstrated this same capability.

Our proprietary cell technology using autologous (a patient’s own naturally occurring) CD34+ cells has led to the development of therapeutic product candidates designed to address diseases and conditions caused by ischemia.

Ischemia occurs when the supply of oxygenated blood to healthy tissue is restricted.

Through the administration of CD34+ cells, we seek to promote the development and formation of new microvasculature and thereby increase blood flow to the impacted area.

We believe that a number of conditions caused by underlying ischemic injury can be improved through our CD34+ cell technology including but not limited to CLI, CMD, NORDA and CKD.

HONEDRA ® for Treatment of Critical Limb Ischemia

Our randomized and open-label, registration-eligible study of HONEDRA ® in Japan for the treatment of CLI has shown strong results to date.

The initial responses observed in the subjects who have reached an endpoint in this open label study are consistent with a positive therapeutic effect and safety profile as reported by previously published clinical trials in Japan.

Although the study's enrollment has been slowed by the COVID-19 pandemic's impact in Japan, we are encouraged by the

patient pre-screening pipeline that has been identified and expect to conclude trial enrollment during the second quarter of 2021.

While the final outcome of the trial will depend on all data from all subjects, data, to date, are very encouraging.

OLOGO TM for Treatment of No Option Refractory Disabling Angina

We acquired the rights to data and regulatory filings for a CD34+ cell therapy program for refractory angina that had been advanced to Phase 3 by a previous sponsor.

Based on the clinical evidence from the completed studies that a single administration of OLOGO TM reduces mortality, improves angina and increases exercise capacity in patients with otherwise untreatable angina, this product received Regenerative Medicine Advanced Therapy (“RMAT”) designation from the FDA.

We remain in discussion with the FDA regarding the size and scope of a phase 3 trial which, in combination with previously filed Phase 1, 2 and 3 data, will be considered for the registration of OLOGO TM .

Notably, the RMAT designation affords the product a 6-month review time for a biologics license application ("BLA"), once submitted.

CLBS16 for Treatment of Coronary Microvascular Dysfunction

In 2017, with the assistance of a $1.9 million grant from the National Institutes of Health (Award Number R44HL135889), we initiated our program for CLBS16 for the treatment of CMD, a disease that afflicts millions of patients with no current targeted treatment options.

That study, the ESCaPE-CMD trial, was a Phase 2a proof-of-concept study that enrolled patients at the Mayo Clinic in Rochester, MN and Cedars-Sinai Medical Center in Los Angeles, CA.

In June 2019, we announced the completion of enrollment in this study.

Results of the first 17 of 20 patients enrolled in this trial who reached 6-month follow-up were presented as a rapid fire oral presentation on November 16, 2019 at the annual meeting of the American Heart Association in Philadelphia, PA by one of the principal investigators, Dr.

Noel Bairey Merz, FACC, FAHA, FESC, the director of the Barbra Streisand Women's Heart Center at Cedars-Sinai in Los Angeles, CA.

That data set showed a positive therapeutic effect with a statistically significant improvement in angina frequency, coronary flow reserve, Canadian Cardiovascular Society Angina Class and Seattle Questionnaire score, as well as an acceptable safety profile.

The full data set from that study was presented at the SCAI 2020 Scientific Sessions Virtual Conference on May 14, 2020 by Dr.

Timothy Henry, FACC, of the Christ Hospital in Cincinnati, Ohio.

In December 2020, we commenced enrollment in our Phase 2b FREEDOM trial of CLBS16 as a therapy for CMD.

The first patient in the study was subsequently treated in January 2021 at The Christ Hospital Health Network in Cincinnati, Ohio.

This 105-patient double-blind randomized and placebo-controlled clinical trial (FREEDOM trial) is designed to further evaluate the efficacy and safety of intracoronary delivery of autologous CD34+ cells in subjects with CMD and without obstructive coronary artery disease.

To our knowledge, this is the first controlled regenerative medicine trial in CMD.

CLBS201 for Treatment of Chronic Kidney Disease

We are planning to file an IND for the clinical study of CLBS201, a CD34+ investigational product for administration into the renal arteries to slow the deterioration or reverse the decline of renal function in patients with chronic kidney disease who, although at a pre-dialysis stage, exhibit rapidly progressive disease.

Progressive kidney failure is associated with attrition of the microcirculation of the kidney.

Pre-clinical studies in kidney disease and injury models have demonstrated that protection or replenishment of the microcirculation results in improved kidney function.

A Phase 2 proof of concept, randomized, placebo-controlled study is being considered for initiation in the 2 nd half of 2021.

Additional Out-licensing Opportunities

Our broad intellectual property portfolio of cell therapy assets includes notable programs available for out-licensing in order to continue their clinical development.

Our current long-term strategy focuses on advancing our therapies through development with the ultimate objective of obtaining market authorizations and entering commercialization, either alone or with partners, to provide treatment options to patients suffering from life-threatening medical conditions.

Coronavirus Considerations

In December 2019, a novel strain of coronavirus (SARS-CoV-2), which causes COVID-19, was reported to have surfaced in China.

In March 2020, the World Health Organization declared the outbreak of COVID-19 to be a pandemic, and the world's economies began to experience pronounced effects.

Despite the FDA approval of multiple COVID-19 vaccines in late 2020, there remains uncertainty around the extent and duration of disruption and any future related financial impact cannot be reasonably estimated at this time.

In response to the pandemic, we have implemented work from home as well as social distancing and other hygiene policies for employees when they must be in the office.

Our clinical study of HONEDRA ® in Japan has experienced delays in enrollment due to the “State of Emergency” in effect in Japan for most of 2020 and re-

implemented in Japan on Jan 7, 2021 and now extending through March 7, 2021 covering Tokyo and other regions in response to increased number of COVID-19 patients.

THE FIELD OF CELL THERAPY

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autologous and allogeneic.

When cells are collected from a person (donor) and transplanted or used to develop a treatment solely for that same person (recipient or patient) with or without modification,

the treatment paradigm is known as “autologous” cell therapy.

When cells are collected from a person (donor) and transplanted or used to develop a treatment solely for that same person (recipient or patient) with or without modification, the treatment paradigm is known as “autologous” cell therapy.

For long-term repair of cardiovascular tissues, evidence indicates that the repair cells must remain in the target tissue for a period of time.

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The FDA has been investing significant resources into policies and organizational changes to advance the cell and gene therapy fields in recent years through what the agency has labeled its “comprehensive regenerative medicine policy framework,” as first announced in late 2017 and incrementally developed since that time through various agency actions.

CELL THERAPY PRODUCT DEVELOPMENT

Ischemic Repair (CD34 Cell Technology)

The CD34+ cell was discovered as a result of the deliberate search for a stem cell capable of stimulating the development and/or repair of blood vessels.

All tissues in the body maintain their function by replacing cells over time.

In addition to the maintenance function, the body must also be capable of building new blood vessels after injury.

A CD34+ cell is a stem cell that has the ability to stimulate new blood vessel formation.

No other native cell discovered to date has demonstrated this same capability.

Our CD34+ cell technology has led to the development of therapeutic product candidates designed to address diseases and conditions caused by ischemia.

Ischemia occurs when the supply of oxygenated blood to healthy tissue is restricted.

Through the administration of CD34+ cells, we seek to promote the development and formation of new microvasculature and thereby increase blood flow to the impacted area.

We believe that a number of conditions caused by underlying ischemic injury can be improved through our CD34+ cell technology, including but not limited to, CLI, CMD and NORDA.

While other cell types have been tested by researchers for the treatment of cardiovascular conditions, none have been shown in nature to perform a cardiovascular repair function.

CLBS12 for Treatment of Critical Limb Ischemia

Following detailed discussion and agreement with the Japanese Pharmaceutical and Medical Device Agency ("PMDA"), we treated the first patient in a registration-eligible trial in Japan in March 2018.

Based on discussions with the PMDA, we expect CLBS12 will be eligible for early conditional approval in Japan if there is a successful outcome of this trial, thereby effectively making the ongoing trial a potential registration trial in that strategic market.

Enrollment is ongoing and we anticipate completion by mid-2020 with top line data targeted for late 2020 or early 2021.

While the data accumulated to date continue to be encouraging, the final outcome of the trial will be dependent on all data from all subjects.

Based on the accelerated review afforded CLBS12 by its SAKIGAKE designation and the current projected timeline to study completion, we expect that CLBS12 could potentially be an approved commercial product in Japan as early as late 2021 or early 2022.

CLBS16 for Treatment of Coronary Microvascular Dysfunction

In October 2017, we announced the award of a $1.9 million grant from the National Institutes of Health to support a clinical study of CD34+ cells in patients with CMD under Award Number R44HL135889.

The content of that announcement is solely our responsibility and does not necessarily represent the official views of the National Institutes of Health.

This award led to the initiation of development of CLBS16 and enrollment of patients in our ESCaPE-CMD Phase 2 proof-of-concept study at the Mayo Clinic in Rochester, MN and Cedars-Sinai Medical Center in Los Angeles, CA.

In June 2019, we announced the completion of enrollment in this study.

Noel Bairey Merz, FACC, FAHA, FESC, the director of the Barbra Streisand Women's Heart Center at Cedars-Sinai in Los Angeles, CA.

We are planning to advance the CLBS16 program to its next clinical development step, a Phase 2b study, with a target for first patient enrolled by mid-2020.

CLBS14 for Treatment of No Option Refractory Disabling Angina (NORDA)

We acquired the rights to data and regulatory filings for a CD34+ cell therapy program for refractory angina that had been advanced to Phase 3 by a previous sponsor.

Based on the clinical evidence from the completed studies that a single administration of CLBS14 reduces mortality, improves angina, and increases exercise capacity in patients with otherwise untreatable angina, this product received RMAT designation from the FDA.

Working closely with the FDA, we have finalized the design of a confirmatory Phase 3 trial which, in combination with previously filed Phase 1, 2 and 3 data, will be considered for the registration of CLBS14.

Notably, this study design includes a 6-month primary endpoint and, with the benefit of the RMAT designation, the biologics license application ("BLA"), once submitted, is expected to receive a 6-month review.

We have completed substantially the preparatory work for initiation of this trial.

We will not, however, commence enrollment of patients until sufficient capital dedicated to this program is acquired by us, which capital will give us confidence that we can fund the trial uninterrupted through completion.

TECHNOLOGY OUT-LICENSING OPPORTUNITIES

Ischemic Repair (CD34+ Cell Technology)

Our CD34+ Cell Technology is a platform technology with potential application to a broad array of ischemic conditions and we will seek to out-license our technology in geographies or indications where we do not intend to pursue development ourselves.

Our CD34+ Cell Technology is an autologous cell platform technology with potential application to a broad array of ischemic conditions and we will seek to out-license our technology in geographies or indications where we do not intend to pursue development ourselves.

Intellectual Property Platform

Our developed and owned ischemic repair patent portfolio comprises the following:

patents, three EU patents (each filed in 5 individual countries) and 7 other patents in Japan, Canada, Russia and Hong Kong;

patents, three EU patents (each filed in 5 individual countries) and ten other patents in Japan, Canada, Russia and Hong Kong;

Claims cover, inter alia , a pharmaceutical composition that contains a therapeutic concentration of non-expanded CD34+ stem cells that move in response to SDF-1 or VEGF, together with a stabilizing amount of serum, that can be delivered to repair an injury caused by vascular insufficiency;

Issued and pending claims can be applied to a broad range of conditions caused by underlying ischemia, including:

acute myocardial infarction;

chronic myocardial ischemia post-AMI;

chronic heart failure;

critical limb ischemia;

and ischemic brain injury;

Two pending patent applications outside the United States.

Issued and pending claims can be applied to a broad range of conditions caused by underlying ischemia, including acute myocardial infarction, chronic myocardial ischemia post-AMI, chronic heart failure, critical limb ischemia, and ischemic brain injury;

One pending patent application outside the United States.

Market Opportunity for CLI

In Japan, there are approximately 300,000 patients with CLI, of whom approximately 51,000 are not candidates for revascularization, making them the addressable population for CLBS12.

The addressable population is approximately 560,000 patients in the EU and 300,000 in the U.S.

In Japan, there are approximately 300,000 patients with CLI, of whom approximately 51,000 are not candidates for revascularization, making the addressable population for HONEDRA ® approximately 560,000 patients in the EU and 300,000 in the U.S.

The field of cardiovascular cell therapy development is competitive.

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fat, peripheral blood, cord blood, and bone marrow.

CLBS12 is an autologous therapy that derives its cells from peripheral blood via apheresis.

HONEDRA ® is an autologous therapy that derives its cells from the peripheral blood of the patient via apheresis.

Market Opportunity for CMD

In the United States, there are approximately 8,300,000 patients with CMD, while the addressable population is roughly 6,000,000 in the EU and 1,000,000 in Japan.

In the United States, there is an addressable population of approximately 400,000 to 1,600,000 patients with CMD, while the addressable population is roughly 1,200,000 to 4,800,000 in the EU and between 43,000 and 166,000 in Japan.

Market Opportunity for NORDA

In the United States, we have identified fewer than 100,000 patients with no-option refractory disabling angina as candidates for CLBS14, making this an indication of orphan size.

In the United States, we have identified fewer than 100,000 patients with no-option refractory disabling angina as candidates for OLOGO TM , making this an indication of orphan size.

Market Opportunity for CKD

In the United States, stages 3 and 4 CKD patients represent an addressable population of approximately 15,000,000 to 18,000,000 and there is an estimated addressable population of 11,500,000 to 14,200,000 patients in the EU.

GOVERNMENT REGULATION

The health care industry is one of the most highly regulated industries in the United States and abroad.

The healthcare industry is one of the most highly regulated industries in the United States and abroad.

Various governmental regulatory authorities, as well as private accreditation organizations, oversee and monitor the activities of individuals and businesses engaged in the development, manufacture and delivery of health care products and services.

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• completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA's good laboratory practice or GLP regulations;

submission to the FDA of an IND, which includes the detailed clinical protocol and which must take effect before human clinical trials can commence;

• submission to the FDA of an IND, which includes the detailed clinical protocol, which must take effect before human clinical trials can commence;

• approval of the clinical trial protocol and the sponsor's safeguards for human subjects by one or more institutional review boards, or "IRBs," depending on the numbers of clinical sites and other features of the study design, before each clinical trial may be initiated;

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Submission of an NDA or BLA to the FDA

Assuming successful completion of the required clinical testing, the results of the preclinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA or BLA seeking approval to market the drug product for one or more indications.

other things, are submitted to the FDA as part of an NDA or BLA seeking approval to market the drug product for one or more indications.

FDA approval of the NDA or BLA is required before marketing of the product may begin in the United States.

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To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected benefit of the product, expected duration of treatment, seriousness of known or potential adverse events, and whether the product is a new molecular entity.

REMS requirements are tailored to the specific risk/benefit profile of a drug and can include requirements such as medication guides for patients, detailed communication plans for health care professionals, and elements to assure safe use, or “ETASU.” ETASU may include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, restricted distribution, and the use of patient registries.

include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, restricted distribution, and the use of patient registries.

The FDA may require a REMS as a condition of approval or may add such a requirement at any point post-approval if it becomes aware of a serious risk associated with use of the product.

The requirement for a REMS and the specific components that are involved can materially affect the potential market and profitability of a product.

If the FDA concludes an REMS plan is needed, the sponsor of the NDA or BLA must submit a proposed REMS.

The FDA will not approve an NDA without an REMS, if required.

If the FDA concludes a REMS plan is needed, the sponsor of the NDA or BLA must submit a proposed REMS.

The FDA will not approve an NDA without a REMS, if required.

Expedited Review Programs (Fast Track, Breakthrough, RMAT) and Accelerated Approval Pathways

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Additionally, the Fast Track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.

Separately, under the FDA’s accelerated approval regulations, the FDA may approve a drug for a serious or life-threatening

illness that provides meaningful therapeutic benefit to patients beyond existing treatments based upon a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

Separately, under the FDA’s accelerated approval regulations, the FDA may approve a drug for a serious or life-threatening illness that provides meaningful therapeutic benefit to patients beyond existing treatments based upon a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

In clinical trials, a surrogate endpoint is a measurement of laboratory or clinical signs of a disease or condition that substitutes for a direct measurement of how a patient feels, functions or survives.

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Under the Pediatric Research Equity Act ("PREA"), NDAs or BLAs or supplements to NDAs or BLAs must contain data that are adequate to assess the safety and effectiveness of the drug or biologic for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the drug is safe and effective.

Sponsors must also submit pediatric trial plans prior to the assessment data, and those plans must contain an outline of the proposed pediatric trial or trials the applicant plans to conduct, including trial objectives and design, any deferral or waiver requests and other information required by regulation.

Sponsors must also submit pediatric trial plans prior to the assessment data, and those plans must contain an

outline of the proposed pediatric trial or trials the applicant plans to conduct, including trial objectives and design, any deferral or waiver requests and other information required by regulation.

The applicant, the FDA, and the FDA’s internal review committee must then review the information submitted, consult with each other, and agree upon a final plan.

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Applications under the BPCA are treated as priority applications, with all of the benefits that designation confers.

Under the Orphan Drug Act, the FDA may designate a candidate as an orphan drug if it is intended to treat a rare disease or condition (generally meaning that it affects fewer than 200,000 individuals in the U.S.) Orphan drug designation must be

requested by an applicant before submitting an NDA or BLA for the relevant drug candidate.

If the FDA grants orphan drug designation, the FDA will publicly disclose the generic identity of the drug candidate and its potential orphan use.

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These manufacturers must comply with cGMP regulations that require, among other things, quality control and quality assurance, the maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain cGMP/cGTP compliance and ensure ongoing compliance with other statutory requirements the FD&C Act, such as the requirements for making manufacturing changes to an approved NDA or BLA.

Accordingly, manufacturers must continue to expend time, money and effort in the area of production

and quality control to maintain cGMP/cGTP compliance and ensure ongoing compliance with other statutory requirements the FD&C Act, such as the requirements for making manufacturing changes to an approved NDA or BLA.

Even after a new drug or biologic approval is granted, the FDA may withdraw that approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

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This conditional approval is time-limited, and there must be an agreement with PMDA/MHLW as to follow-up collection of information which confirms efficacy and safety, similar to a post-marketing commitment in the United States.

Under the PMD Act, products under consideration may also be given a SAKIGAKE designation (similar to an FDA "Breakthrough" or "RMAT" designation in certain respects) and/or may be granted a priority review status.

Under the PMD Act, products under consideration may also be given a SAKIGAKE designation (similar to an FDA "Breakthrough" or "RMAT" designation in certain respects) with a priority 6 months review period.

Additionally, there is a commitment that the PMDA will facilitate research and development by giving scientific and regulatory advice to sponsors from the early stage of development.

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This procedure is followed for both a conditional approval and subsequently for a full approval after the post-marketing commitments have been fulfilled.

SUMMARY OF RISK FACTORS

Our business, financial condition, operating results and cash flows are subject to numerous risks and uncertainties that are summarized below.

The below summary of risk factors should be read together with the more detailed discussion of risks set forth following this section under the heading “Risk Factors,” as well as elsewhere in this Annual Report on Form 10-K.

• We have incurred substantial losses and negative cash flow from operations in the past and expect to continue to incur losses and negative cash flow for the foreseeable future.

Additionally, we anticipate that we will need substantial

additional financing to continue our operations;

if we are unable to raise additional capital, we may be forced to delay, reduce or eliminate one or more of our product development programs, and our business will be harmed.

• If our status as a smaller reporting company changes, Section 404(b) of the Sarbanes-Oxley Act of 2002 may require an independent registered public accounting firm to report on the effectiveness of our internal control over financial reporting.

Any delays or difficulty in satisfying these requirements could adversely affect our future results of operations and our stock price.

• Our future success may be dependent on the timely and successful continued development and commercialization of HONEDRA®, our experimental product candidate for CLI and Buerger's Disease that is in clinical development in Japan, CLBS16 for CMD, CLBS201 for CKD and OLOGO TM for NORDA, and if we encounter delays or further difficulties in the development of these product candidates, our business prospects would be significantly harmed.

• Our business has been and may continue to be adversely affected by the COVID-19 pandemic.

• We may experience delays in completing our clinical trials and in enrolling patients in our clinical trials, which could delay or prevent the receipt of necessary regulatory approvals.

• We may be unable to manage multiple late stage clinical trials for a variety of product candidates simultaneously.

• The development of our cell therapy product candidates is subject to uncertainty because autologous cell therapy is inherently variable.

• Any disruption to our access to the reagents we are using in the clinical development of our cell therapy product candidates could adversely affect our ability to perform clinical trials and seek future regulatory submissions.

• The initiation of pivotal Phase 3 clinical trials for cell therapy product candidates requires the validation and establishment of manufacturing controls that may delay product development timelines.

• If serious or unacceptable side effects are identified during the development of any of our product candidate, we may need to abandon or limit our development of that product candidate.

• A Fast Track designation by the FDA and other similar regulatory designations may not lead to a faster development, regulatory review or approval process.

• Our clinical trials may fail to demonstrate adequately the safety and efficacy of our product candidates, which would prevent or delay regulatory approval and commercialization.

• We presently rely on contract manufacturing organizations to produce our product candidates at development and commercial scale quantities and have not yet qualified an alternate manufacturing supply, which could negatively impact our ability to meet any future demand for the products.

• We may form or seek collaborations or strategic alliances or enter into additional licensing arrangements in the future, and we may not realize the benefits of such alliances or licensing arrangements.

• Our cell therapy business is based on novel technologies that are inherently expensive, risky and may not be understood by or accepted in the marketplace, which could adversely affect our future value.

• If competitors develop and market products that are more effective, safer, or less expensive than our product candidates or offer other advantages, our commercial prospects will be limited.

• We may be subject to significant product liability claims and litigation, including potential exposure from the use of our product candidates in human subjects, and our insurance may be inadequate to cover claims that may arise.

• We may be unable to retain key officers or employees or hire new key officers or employees needed to implement our business strategy and develop our products and businesses.

• Our internal computer systems, or those used by our clinical investigators, clinical research organizations or other contractors or consultants, may fail or suffer security breaches, which could result in a material disruption of development programs for our product candidates.

Additionally, the increasing use of social media platforms presents new risks and challenges.

• Contract development and manufacturing organizations have a finite cell manufacturing capacity, which could inhibit the long-term growth prospects of our business and we will need to improve manufacturing efficiency at our contract manufacturers in order to establish cost of goods levels that will permit approved products to succeed commercially.

• The development and commercialization of our product candidates are subject to extensive regulation by the FDA and other regulatory agencies in the United States and abroad, and the failure to receive regulatory approvals for our cell therapy product candidates would likely have a material and adverse effect on our business and prospects.

• We may be subject to numerous and varying privacy and security laws, and our failure to comply could result in penalties and reputational damage.

• We will continue to be subject to extensive regulation following any product approvals, and if we fail to comply with these regulations, we may suffer a significant setback in our business.

• Health care companies have been the subject of federal and state investigations, and we could become subject to investigations in the future.

• It is uncertain to what extent government, private health insurers and third-party payors will approve coverage or provide reimbursement for the therapies and products to which our research and development relate.

Availability for such reimbursement may be further limited by an increasing uninsured population and reductions in Medicare and Medicaid funding in the United States.

• Competitor companies or hospitals may be able to take advantage of EU rules permitting sales of unlicensed medicines for individual patients to sell competing products without a marketing authorization.

• We may be unable to obtain or maintain patent protection for our products and product candidates, which could have a material adverse effect on our business.

• Litigation and third-party claims relating to intellectual property is expensive, time-consuming and uncertain, and we may be unsuccessful in our efforts to protect against infringement by third parties or defend ourselves against claims of infringement.

• In certain countries, patent holders may be required to grant compulsory licenses, which would likely have a significant and detrimental effect on any future revenues in such country.

• Our stock price has been, and will likely continue to be, highly volatile.

• In addition to potential dilution associated with future fundraising transactions, we currently have significant numbers of securities outstanding that are exercisable for our common stock, which could result in significant additional dilution and downward pressure on our stock price.

• Provisions in our amended and restated certificate of incorporation and by-laws and Delaware law may inhibit a takeover of us, which could limit the price investors might be willing to pay in the future for our common stock and could entrench management.

• Failure to maintain effective internal control over financial reporting in accordance with Section 404 of the Sarbanes-Oxley Act could have a material adverse effect on our business and stock price.

• We may fail to comply with the continued listing requirements of the Nasdaq Capital Market, such that our common stock may be delisted and the price of our common stock and our ability to access the capital markets could be negatively impacted.

As of December 31, 2020, we had 24 full-time employees.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business