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Item 1. Business

2024-04-16 compared with 2023-03-30 · 263 added, 365 removed, 441 unchanged (59% of the section changed)

Unless the context otherwise requires, all references in this section to "SeaStar Medical," the “Company,”

“we,”

“us”

or “our”

refer to SeaStar Medical Holding Corporation and its consolidated subsidiaries following the Business Combination (as defined herein), other than certain historical information that refers to the business of SeaStar Medical prior t0o the consummation of the Business Combination.

We are a medical technology company developing a platform therapy to reduce the consequences of hyperinflammation on vital organs.

Unless the context otherwise requires, all references in this section to "SeaStar Medical," the “Company,” “we,” “us” or “our” refer to SeaStar Medical Holding Corporation and its consolidated subsidiaries following the Business Combination (as defined herein), other than certain historical information that refers to the business of SeaStar Medical, Inc.

(the “Predecessor”) prior to the consummation of the Business Combination.

We are a clinical stage medical technology company developing a proprietary platform therapy, our Selective Cytopheretic Device (“SCD”), to reduce the consequences of hyperinflammation on vital organs.

The inflammatory response is critical to fend off infections and repair damaged tissue in the body.

Central to inflammation are the cells within blood and lymph circulatory systems, called white blood cells (primarily neutrophils and monocytes) or also referred to commonly as “pus”

Central to inflammation are the cells within blood and lymph circulatory systems, called white blood cells (primarily neutrophils and monocytes), also referred to commonly as “pus” cells.

In a normal inflammatory response, neutrophils are the first immune cells to arrive at the site and are key to the entire immune response that kills pathogens and promotes tissue repair.

These inflammatory cell release chemicals (cytokines) which trigger the immune system to eliminate the foreign pathogens or damaged tissue, enhancing the immune response.

If the inflammatory response becomes excessive and dysregulated (referred as proinflammatory), normal neutrophil die off (“apoptosis”) may be delayed, allowing the inflammatory cells to continue to produce cytokines further enhancing the dysregulated immune response, altering feedback mechanisms that regulate the immune system.

These inflammatory cells release chemicals (cytokines) that trigger the immune system to eliminate the foreign pathogens or damaged tissue, enhancing the immune response.

If the inflammatory response becomes excessive and dysregulated (referred as proinflammatory), normal neutrophil cells die off (“apoptosis”), allowing the inflammatory cells to continue to produce cytokines, further enhancing the dysregulated immune response, and altering feedback mechanisms that regulate the immune system.

This results in damaging hyperinflammation spreading uncontrollably to other parts of the body, often leading to acute chronic solid organ dysfunction or failure, including heart, lung, kidney and liver diseases.

This hyperinflammatory response is also known as the “cytokine storm,”

referring to the body’s reaction to the category of small-secreted proteins released by hyperinflammatory cells that affect communication between cells.

This hyperinflammatory response is also known as the “cytokine storm,” referring to the body’s reaction to the category of small-secreted proteins released by hyperinflammatory cells that affect communication between cells.

The cytokine storm, when left uncontrolled, can lead to organ damage and even death.

Based on clinical and preclinical studies conducted over the last 15 years, the Company’s technology has shown promise in modulating the degree of activity of proinflammatory cells to help reduce tissue damage and speed the repair and recovery of organ function.

We believe this approach, if successful, will transform the ability of clinicians to treat acute organ failure in the intensive care unit (“ICU”) and to improve organ function in hospitalized patients.

Currently few therapeutics are available to clinicians to address the issue of hyperinflammation and for those options that do exist, such options are either immunosuppressive or only target one cytokine.

We believe our technology has the potential to overcome limitations in existing anti-inflammatory treatments and address the challenge in selectively targeting activated neutrophils and monocytes.

We are leveraging our patent protected and scalable technology platform to develop proprietary therapies that are organ agnostic and target both acute and chronic indications.

We are using our proprietary Selective Cytopheretic Device ("SCD") technology platform initially to clinically validate several acute organ injury indications, including kidneys and lungs.

Currently, few therapeutics are available to clinicians to address hyperinflammation and for those options that do exist, such options are either immunosuppressive or only target one cytokine.

We believe our technology has the potential to overcome limitations in existing anti-inflammatory treatments and address the challenge of selectively targeting activated neutrophils and monocytes.

We are leveraging our patent protected and scalable SCD technology platform to develop proprietary therapies that are organ agnostic and target both acute and chronic indications.

Preclinically, our SCD was tested in various animal models, which include acute myocardial infarction, intracranial hemorrhage, chronic heart failure, sepsis, and acute respiratory distress syndrome.

The animal models demonstrated the inflammatory response and how it was modified by our SCD.

We will continue to explore the application of our SCD technology across a broad range of markets and indications where proinflammatory activated neutrophils and monocytes may contribute to disease progression or severity in both acute and chronic indications.

We are using our SCD initially to clinically validate several acute organ injury indications, including kidneys and lungs.

Our investigational SCD is an extracorporeal synthetic membrane device designed to be easily integrated into existing continuous renal replacement therapy ("CRRT") systems that are commonly installed in hospitals, including in ICUs throughout the United States.

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In addition, we are developing our SCD to address inflammation associated with chronic dialysis and chronic heart failure.

Preclinically, our SCD was tested in various animal models, which include acute myocardial infarction, intracranial hemorrhage, chronic heart failure, sepsis and acute respiratory distress syndrome.

The animal models showed the inflammatory response and how it was modified by our SCD.

There is substantial clinical demand for safe and effective control of hyperinflammation.

Existing treatment options in hyperinflammation include the use of corticosteroids (immunosuppression) and absorbent technologies that either directly absorb cytokines, viruses, bacteria or endotoxins and pharmaceuticals that target cytokines and the immune cascade.

None selectively addresses activated neutrophils or monocytes.

The use of our SCD to reverse the cytokine storm in pediatric and adult patients with acute kidney injury on CRRT in clinical studies with more than 140

patients reduced mortality rates by 50%, and, of those patients who survive 60 days, none have required dialysis.

The unique mechanism of action (modulation of neutrophils and monocytes) has exhibited consistent clinical outcomes in both adults as well as children.

Given the clinical advantages of our SCD, we believe our SCD has the potential to become a preferred course of treatment by clinicians for hyperinflammatory indications based on its potential to improve patient outcomes, increase survival rates, reduce dialysis dependence, and ultimately lower healthcare costs.

As of December 31, 2022, our SCD has been used in approximately 170 adult and pediatric patients on an investigational basis.

The use of our SCD to reverse the cytokine storm in pediatric and adult patients with acute kidney injury on CRRT in clinical studies with more than 140 patients reduced mortality rates by 50%, and, of those patients who survive 60 days, none have required dialysis.

In June 2022, we submitted a humanitarian device exemption ("HDE") application with the U.S.

Food & Drug Administration ("FDA") for pediatric patients with acute kidney injury ("AKI") on CRRT.

Based on the current timeline of the HDE application, we expect the FDA to complete its substantive review of our HDE application during the first half of 2023;

however, there is no guarantee that the FDA will approve our HDE application.

On February 22, 2024, we received the FDA HDE Approval Order, which allows sales to qualified healthcare facilities.

We intend to continue to shape our commercial and distribution strategy by expanding indications and pursue collaborations with partners in markets where such partners provide strategic capabilities in commercializing our product candidates and enabling access to specific patient populations.

On December 27, 2022, we entered into a license and distribution agreement (the “Distribution Agreement”) with Nuwellis, Inc.

(“Nuwellis”), pursuant to which we appointed Nuwellis as our exclusive distributor for the sale and distribution of our pediatric SCD product throughout the United States once we receive from the FDA a written authorization to market such product for pediatric use pursuant to our HDE application.

Pursuant to the Distribution Agreement, we received an upfront payment , and will receive milestone payments upon achievement of certain milestones and royalties on gross sales of the SCD product.

The Distribution Agreement has an initial term commencing on December 27, 2022 and shall end on the three (3) year anniversary from the date that is the earlier of (a) ninety (90) days after we receive FDA authorization to market such SCD product for pediatric use and (b) the first commercial sale of the SCD product.

The term of the Distribution Agreement may be automatically extended for additional terms of one (1) year and for a total of two (2) consecutive extensions.

Each party has the right to terminate the Distribution Agreement for material breach if such breach is not cured within ninety (90) days after written notice and we have additional rights to terminate the Distribution Agreement in accordance with other terms set forth in the Distribution Agreement.

On December 29, 2023, the Distribution Agreement was amended and the Distributor shall pay Supplier the following milestone payments set forth below on the later to occur of (i) 30 days after achievement of the corresponding milestone events or April 1, 2024, and the Distributor has waived the repayment of the upfront payment from Supplier.

In addition, on February 9, 2023, we received approval from the FDA of our investigational device exemption ("IDE") application to conduct a pivotal study evaluating the effectiveness of SCD in reducing hyperinflammation in adults with AKI requiring CRRT.

The Company plans to begin enrollment in Q2 2023 and expect to generate interim study results during the fourth quarter of 2023 and topline study results and submission of a Pre-market Approval ("PMA") application in the second half of 2024.

On April 29, 2022, we received a Breakthrough Device Designation ("BDD") for the use of our SCD in the treatment of immunomodulatory dysregulation in adult patients (18 and older) with AKI, which is expected to accelerate the regulatory approval process for such trial.

The Company began enrollment in Q2 2023 and expect to generate interim study results during the second half of 2024 and topline study results and submission of a Pre-market Approval ("PMA") application in the first half of 2025.

There is no guarantee that we will complete the AKI adult trial in a timely manner, or at all, nor will there be any assurance that positive data will be generated from such trial.

Even if we are able to generate positive results from these trials, the FDA may require us to conduct additional trials to support the study, or disagree with the design of the trials and request changes or improvements to such design.

We believe that our novel therapeutic device is readily applicable for use in other indications, which will require additional clinical studies and FDA approval.

We have received two additional Breakthrough Device Designations ("BDD") in 2023, totaling three.

On September 28, 2023, we received Breakthrough Device Designation for our patented and cell-directed SCD for use with patients in the hospital ICU with acute or chronic systolic heart failure and worsening renal function due to cardiorenal syndrome or right ventricular dysfunction awaiting implantation of a left ventricular assist device.

On October 18, 2023, we received Breakthrough Device Designation for our patented and cell-directed SCD for use with patients in the hospital ICU with AKI and acute on chronic liver failure.

We have been granted three

Breakthrough Device Designations from the FDA for the SCD device, each of which is expected to expedite the clinical development and regulatory review of the SCD for use in the designated patient population.

We believe that our novel therapeutic device is readily applicable for use in other indications, which will require additional clinical studies and FDA approval and increase the addressable market for our SCD technology.

As we continue our work to expand indications, we believe we will have the ability to take advantage of economies of scale to reduce costs of production.

We believe our scalable manufacturing process demonstrates a significant competitive advantage in the hyperinflammatory market.

We have pursued patent protection for our SCD technology as well as other technologies, which consists of 40 patents and 10 pending patent applications in the U.S.

We have pursued patent protection for our SCD technology as well as other technologies.

Our patent portfolio consists of 40 patents and 8 pending patent applications in the U.S.

and certain foreign jurisdictions.

Of these patents and patent applications 33 are owned exclusively by us, and 15 are co-owned with the University of Michigan ("UOM").

UOM has granted to us an exclusive worldwide, royalty bearing license to UOM’s interest in all of the co-owned patents and applications.

This license permits us to commercialize our SCD in all human therapeutic indications.

For more information, see “

Intellectual Property ”

We intend to continue to shape our commercial and distribution strategy by expanding indications and pursue collaborations with partners in markets where such partners provide strategic capabilities in launching our product candidates and enabling access to specific patient populations.

On December 27, 2022, we entered into a license and distribution agreement (the “Distribution Agreement”) with Nuwellis, Inc.

(“Nuwellis”), pursuant to which we appointed Nuwellis as our exclusive distributor for the sale and distribution of SCD product throughout the United States once we receive from the FDA a written authorization to market such product for pediatric use pursuant to our HDE application.

Pursuant to the Distribution Agreement, we received an upfront payment, and will receive milestone payments upon achievement of certain milestones and royalties on gross sales of the SCD product.

The term of the Distribution Agreement may be automatically extended for additional terms of one (1) year and for a total of two (2) extensions.

UOM has granted to us an exclusive worldwide, royalty bearing license to UOM’s interest in all of the co-owned patents and applications.

This license permits the Company to commercialize our SCD in all human therapeutic indications.

For more information, see “ — Intellectual Property” below.

Our senior management team and Board have an average of more than 19 years of experience in the healthcare industry, including expertise in medical affairs, commercialization and distribution in our initial therapeutic priority areas.

We are also supported by a group of well-respected scientific advisors who are experts in the development of our technology and products.

Corporate History

SeaStar Medical, Inc.

was initially incorporated under the name Nephrion, Inc.

on June 6, 2007.

On August 3, 2007, we amended our corporate name to CytoPherx, Inc.

On June 19, 2019, we amended our corporate name to SeaStar Medical, Inc.

On October 28, 2022, LMF Acquisition Opportunities, Inc.

(“LMAO”), a Delaware corporation, consummated a series of transactions that resulted in the combination of LMF Merger Sub, Inc., a Delaware corporation and a wholly-owned subsidiary of LMAO (“Merger Sub”), and SeaStar Medical, Inc., a Delaware corporation, pursuant to an Agreement and Plan of Merger, dated April 21, 2022 (the “Merger Agreement”), by and among LMAO, Merger Sub and SeaStar Medical, Inc.

(the "Closing").

Pursuant to the terms of the Merger Agreement, a business combination between LMAO and SeaStar Medical, Inc.

was affected through the merger of Merger Sub with and into SeaStar Medical, Inc., with SeaStar Medical, Inc.

surviving the merger as a wholly-owned subsidiary of LMAO (the “Business Combination”).

Following the consummation of the Business Combination, LMAO was renamed “SeaStar Medical Holding Corporation”

(the “Company”).

The acute inflammatory response occurs in a well-defined coordinated sequential response.

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The first are proinflammatory macrophages, followed by patrolling, reparative macrophages.

This complex tightly coordinated process is critical for host defense and tissue repair but needs to be tightly regulated by the body’s inflammatory signaling and cellular apoptosis.

If not, further tissue destruction may occur when uncontrolled hyperinflammation leads to degradative reparative processes with worsening tissue or organ function.

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the standard hemofilter cartridge enters our SCD and disperses among the fibers of the device.

Upon exiting our SCD under a low calcium environment, the blood is returned to the patient’s body.

Our SCD delivers its therapeutic benefit by attenuating the excessive inflammatory response of activated neutrophils and monocytes.

Uninterrupted, the excessive inflammatory response progresses to multi-organ failure (“MOF”), with documented increases in both morbidity and mortality in critically ill patients.

Our initial lead product is focused on critically ill AKI pediatric and adult patients on CRRT.

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Our Market Opportunity

We are a therapeutic medical device company with clinical data collected and available to support a HDE submission to the FDA to request the use of our SCD in pediatric patients with AKI and additional clinical data intended to support the initiation of a pivotal PMA study in adult AKI.

In the long term, we intend to pursue the application of our SCD technology to additional indications, including, but not limited to, acute respiratory distress syndrome, chronic dialysis, cardiorenal syndrome and hepatorenal syndrome.

We are a therapeutic medical device company.

Our clinical data was used to support an HDE submission to the FDA to request approval to market our SCD to hospitals and clinicians with pediatric patients suffering from AKI.

Our clinical data has also been used to support the initiation of a pivotal PMA study in adult AKI.

In the long term, we intend to pursue the application of our SCD technology to additional indications, including acute respiratory distress syndrome, chronic dialysis, cardiorenal syndrome and hepatorenal syndrome and others.

Our Initial Market Opportunity in Acute Kidney Injury

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A 2017 study by Samuel A.

Silver and Glenn M Chertow titled “The Economic Consequences of Acute Kidney Injury”

stated hospital costs associated with AKI in the U.S.

Silver and Glenn M Chertow titled “The Economic Consequences of Acute Kidney Injury” stated hospital costs associated with AKI in the U.S.

are between $5.4 billion and $20 billion per year.

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They do not present clear symptoms or tell the body they are suffering like other major organs such as the heart or lungs.

For example, one does not feel pain with a “kidney attack”

and symptoms are delayed until irreversible damage may have already occurred.

For example, one does not feel pain with a “kidney attack” and symptoms are delayed until irreversible damage may have already occurred.

Kidneys also refrain from revealing the impact to the rest of body and organs (and vice-versa) and often are not considered systemically for co-treatment.

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and Baxter International, which represent over 80% of the market today in the U.S.

Since 2010, a significant amount of data has been published to quantify the clinical and financial impact of AKI, resulting in a broadening AKI treatment “boom”

beyond dialysis to areas of diagnostics, complimentary therapies, and pharmacologics.

As hospital administrators and government officials’

understanding of the impact and burden of AKI increases, we believe that attention will only continue to grow.

According to Hobson in his article titled “Cost and Mortality Associated with Postoperative Acute Kidney Injury,”

a 2015 study of 50,314 patients (over 11 years) found that upon greater scrutiny, AKI was found in 39% of post-surgical patients, and 19% of patients had stage 2 or 3 AKI with an average incremental cost of $29,800 per patient.

Since 2010, a significant amount of data has been published to quantify the clinical and financial impact of AKI, resulting in a broadening AKI treatment “boom” beyond dialysis to areas of diagnostics, complimentary therapies, and pharmacologics.

As hospital administrators and government officials gain understanding of the impact and burden of AKI increases, we believe that attention will continue to grow.

According to Hobson in his article titled “Cost and Mortality Associated with Postoperative Acute Kidney Injury,” a 2015 study of 50,314 patients (over 11 years) found that upon greater scrutiny, AKI was found in 39% of post-surgical patients, and 19% of patients had stage 2 or 3 AKI with an average incremental cost of $29,800 per patient.

Additionally, with historical mortality rates approximately 50%, treating AKI is increasingly of interest to clinicians, hospitals, and product manufacturers alike.

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federal agency.

According to Massicotte and Azarniouch in their 2015 work titled “Acute Kidney Injury in the Intensive Care Unit:

Risk Factors and Outcomes of Physician Recognition Compared with KDIGO Classification,”

around 80% of moderate or severe cases of AKI are not diagnosed and documented, suggesting the U.S.

According to Massicotte and Azarniouch in their 2015 work titled “Acute Kidney Injury in the Intensive Care Unit:

Risk Factors and Outcomes of Physician Recognition Compared with KDIGO Classification,” around 80% of moderate or severe cases of AKI are not diagnosed and documented, suggesting the U.S.

AKI patient population is higher than the estimated 6 million patients annually.

The pediatric population for AKI patients on CRRT is estimated to be less than 8,000 patients per year, which is a substantially small sub-set of the 6 million AKI patient population.

The AKI market needs new and effective solutions, and hospitals continue to search and evaluate new products.

The pediatric population for AKI patients in the U.S.

is estimated to be less than 8,000 patients per year, which is a substantially small sub-set of the 6 million AKI patient population.

The AKI market needs new and effective solutions, and hospitals continue to search for and evaluate new products.

For a product to succeed in the AKI space, it must demonstrate and achieve clear and significant clinical benefit to patients, while providing positive financial incentives for hospitals to generate revenue and profitability.

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We expect to employ several core growth strategies:

Execute on the clinical plan through key relationships:

• Execute on clinical plan through key relationships:

Our initial focus on the treatment of AKI in adults and pediatrics is supported by our long and established relationship with UOM, which licenses to us certain key technology underpinning our novel immunomodulatory therapy, as well as other leading academic hospitals and institutions throughout the U.S.

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In addition, we have submitted the HDE for the pediatric AKI indication in June 2022.

On February 22, 2024, we received the FDA HDE Approval Order, which allows sales to qualified healthcare facilities.

In February 2023, the Company received FDA IDE approval for the adult AKI indication.

This indication has received the FDA BDD for our SCD therapy targeting AKI adult patients, is expected to accelerate and streamline the regulatory approval process prior to the commercial launch of our product candidates.

On October 18, 2023, we received Breakthrough Device Designation for our patented and cell-directed SCD for use with patients in the hospital ICU with AKI and acute on chronic liver failure.

We have been granted three Breakthrough Device Designations from the FDA for the SCD device, each of which is expected to expedite the clinical development and regulatory review of the SCD for use in the designated patient population.

• Differentiation through medical education:

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Our Clinical Stage Product Candidates

The following disclosure summarizes our SCD product candidates in clinical stages and other clinical studies.

The following disclosure summarizes the key clinical studies in which our SCD product candidates (Quelimmune for pediatrics) have been evaluated.

All trials and studies below are conducted under IDEs approved by the FDA.

We submitted an HDE application for SCD for the treatment of pediatric patients with acute kidney injury undergoing CRRT with the FDA in June 2022.

We expect the FDA to complete substantive review of the HDE application by the first half of 2023.

We submitted an HDE application for our SCD for the treatment of pediatric patients with acute kidney injury undergoing Continuous Renal Replacement Therapy (CRRT) to the FDA in June 2022.

We obtained an Approvable Letter for the HDE in October 2023.

On February 23, 2024, we announced a final Approval Order for the HDE.

Clinical Progression

SCD 006 Pivotal Study (“SCD 006”) Design

We are in the process of initiating a pivotal clinical trial of the SCD for the treatment of AKI in adults under the recent grant of BDD by the FDA.

This trial ("SCD 006") is a 200 patient, pivotal, prospective, multi-center, open

label, randomized, two-arm comparative study conducted in the United States.

The SCD 006 trial is designed to assess a composite endpoint of both mortality and dialysis dependency at Day 60.

Our target population will be adults with AKI in ICUs in hospital settings and has an estimated 60-day mortality rate of 40% to 50% and for those who survive, the probability of requiring dialysis at Day 60 will be 25%.

SCD 006 Pivotal Study (“SCD 006”) Design

We are actively enrolling and treating patients in a pivotal clinical trial of the SCD for the treatment of AKI in adults under a granted Breakthrough Device Designation (BDD) (April 2022) by the FDA.

This trial ("SCD-006";

NCT05758077) is a 200 subject, prospective, multi-center, open label, randomized, two-arm comparative pivotal study conducted in the United States.

SCD-006 is designed to assess a composite endpoint of both mortality or dialysis dependency at Day 90 (see schematic figure below).

The control arm will consist of adults with AKI who undergo CRRT in hospital ICUs who typically have estimated mortality of nearly 50%.

Among those with AKI who undergo CRRT and survive hospitalization, nearly one in four (25%) usually require long term dialysis.

The study design was recently published in the journal Nephron (Yessayan et al., Nephron.

10.1159/000531880).

The study title is also being referred to as NEUTRALIZE-AKI (NEUTRophil and monocyte deactivation via seLective cytopheretIc device – a randomiZEd clinical trial in Acute Kidney Injury).

Current Trial Status

We submitted the SCD 006 IDE Protocol to the FDA on January 6, 2023.

We anticipate the trial to begin enrollment late in the second quarter of 2023 and is anticipated to complete enrollment in 15 to 18 months.

On April 29, 2022, we received a BDD for the use of our SCD in the treatment of immunomodulatory dysregulation in adult patients (18 and older) with AKI, which should accelerate the regulatory review and approval process for such trial.

We currently anticipate generating interim results from this trial in late 2023 and topline study results and submission of a PMA application in the second half of 2024.

Additional clinical studies under IDEs include cardiorenal syndrome in congested heart failure, myocardial stunning in end-stage renal disease, and hepatorenal syndrome.

We are conducting exploratory clinical research at the University of Michigan to define the patient population for potential treatment with SCD product candidates, and any future studies will be based upon initial clinical data collected in these studies.

Clinical Studies

With the exception of our SCD 003, all of our clinical studies to date have not had a randomized control arm.

AKI Safety, Mortality and Device Integrity Study (CHINA) (ASAIO Journal 57:426-432,2011)

(January 2009 to April 2010)

A study of the SCD was conducted by SeaStar Medical in collaboration with Huashan Hospital in Shanghai, China titled:

An Exploratory Clinical Study to Assess Safety and Efficacy of the Double Hemofiltration Cartridge Device (DCD) in Patients with Acute Renal Failure .

This study was a prospective, non-randomized, interventional study designed to evaluate the effect of treatment with the SCD on in-hospital mortality in the acute renal failure population being treated with CRRT with regional citrate anticoagulation (“RCA”).

Up to seven days of therapy were allowed.

All subjects received standard intensive care treatment for patients undergoing CRRT in addition to the SCD treatment.

In this nine-patient study, the SCD treatment was demonstrated to reduce the mortality rates of ICU patients with AKI in hospitals compared with case-matched controls from a national dataset, based on deaths resulting from all causes in the hospital setting.

The study showed a 22% mortality rates in the SCD treatment arm versus a mortality rate of 78% in the case-matched control group.

This improved survival rate was demonstrated to be independent of age and Sequential Organ Failure Assessment (“SOFA”) Score, which is a scoring system used to predict ICU mortality based on lab results and clinical data.

The results from this study indicated that treatment with SCD was well tolerated, without significant effects on hematological parameters, including white blood cell and platelet counts, and with an adverse event profile that was expected for a seriously ill population in the ICU with AKI.

In the nine subjects analyzed on SCD treatment, no neutropenic events were reported, and no serious adverse events (“SAEs”) were reported.

Adverse events noted included hypercalcemia (8), hypocalcemia (1), hypophosphatemia (2), hypernatremia (1) and thrombocytopenia (1).

A multi-center pilot study to assess the safety and efficacy of a SCD in Patients with Acute Renal Failure (ARF 002) (Seminars in Dialysis Vol 26, Issue 5 :616-623,2013) (May 2010 to January 2011)

This pilot study of the SCD device (ARF-002 Clinical Trial) was sponsored by SeaStar Medical with the support of a third-party contract research organization.

The study was designed to evaluate the safety and efficacy of the SCD treatment after up to seven consecutive 24-hour SCD treatments.

Outcomes were compared to historical data on in-hospital mortality based on all causes of deaths at day 28 and day 60 in the AKI population being treated with CRRT with RCA.

The study enrolled 35 adult subjects.

The mean age was 56.3 and 71.4% of the subjects were Caucasian, 22.9% were Black and 5.7% were Hispanic.

The average SOFA score was 11.3.

The mortality rate from any cause at Day 60 was 31.4% with SCD versus 50% with the historical standard of care based on literature.

Renal recovery, defined as dialysis independence, was observed in all the surviving subjects at Day 60.

Based on the significantly lower mortality rate, the results of this pilot study indicate a potential for a substantial improvement in patient outcomes over historical standard of care therapy.

A total of 199 adverse events (“AEs”) were observed in 33 of the 35 subjects.

Of these 199 AEs, 12 were deemed to be possibly related and one was deemed related (as determined by the investigator) to the study therapy.

These included a worsening coagulation defect, hypotension, neutropenia, disseminated intravascular coagulation (“DIC”), thrombocytopenia, recurrent renal failure, hypophosphatemia, hypercalcemia, anemia, and cardiogenic shock.

Of the 199 total adverse events, 34.7% were deemed to be mild and were experienced by 60% of the subjects, 51.8% were moderate and experienced by 71% of the subjects and 13.6% were severe, experienced by 54% of the subjects.

The AEs observed were those that were expected for a critically ill patient population with acute renal failure and/or in an ICU setting.

Twenty-eight SAEs were observed in 23 subjects (which included death).

There were no unanticipated adverse device effects.

Of these 28 SAEs, two were deemed to be possibly related to treatment (i.e., DIC and cardiogenic shock) and were severe in intensity.

Of the SAEs, seven of the 28, or 25%, were deemed to be moderate and were experienced by 20% of the 35 subjects, and 21 (75%) were deemed to be severe, experienced by 51% of the 35 subjects.

The following table lists all SAEs encountered during the study by category and the assessment of each SAE:

Study Related

List of Serious Adverse Events

Definitely Not

Blood and lymphatic system disorders

Cardiac Disorders

Gastrointestinal Disorders

General disorders and administration site conditions

Infections and infestations

Injury, poisoning and procedural complications

Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders

Nervous system disorders

Renal and Urinary Disorders

Respiratory, thoracic and mediastinal disorders

Vascular Disorders

This was a controlled, randomized, and multicenter clinical trial that was initiated in September 2011 and terminated in September 2013 under an FDA approved IDE.

We submitted the SCD-006 IDE Protocol to the FDA on January 6, 2023 and attained approval in March 2023.

We began enrollment in the second quarter of 2023 and we anticipate the enrollment period to last 15 to 18 months.

On April 29, 2022, we received a BDD for the use of our SCD in the treatment of immunomodulatory dysregulation in adult patients (18 and older) with AKI, which is expected to aide our discussions related to the regulatory review and approval process for SCD-006.

We currently anticipate generating interim results from this trial in late 2024 and topline study results and submission of a PMA application by early 2026.

Additional clinical studies under IDEs include cardiorenal syndrome and hepatorenal syndrome.

We are also conducting exploratory clinical research at the University of Michigan to define the patient population for potential treatment with SCD product candidates, and any future studies will be based upon initial clinical data collected in these studies.

Other Clinical Studies

The table below lists the major studies conducted in AKI to date with our SCD.

Except for SCD-003 and SCD-006, our clinical studies have not included a randomized control arm.

Primary Endpoint

Study Population

Total Enrolled

Device-Related SAEs

AKI Safety, Mortality and Device Integrity Study

Safety and in-hospital mortality

The mortality for the case-matched controls was 77% (7/9), vs 22% (2/9) in the SCD treatment group ( P =0.027) (Ding F, et al.

2011;57(5):426-432).

AKI Safety, Mortality and Device Integrity Study

Safety and 60-day survival

Death from any cause at day 60 was 31.4% (11/35).

Renal recovery, defined as dialysis independence, was observed in all of the surviving subjects at day 60.

(Standard of care therapy is associated with a >50% 60-day mortality (Tumlin JA, et al.

2013;26(5):616-623).

To determine the difference between SCD therapy and CKRT alone in survival

Day 60 survival

This was a Phase 3A randomized controlled trial.

Due to a nationwide calcium shortage during the study, most patients received ineffective therapy as regional ionized calcium (iCa) levels couldn’t be maintained at the target range.

This resulted in no differences in outcomes in the intent-to-treat patient population.

However, the subset of patients who achieved the target iCa ranges showed a significant clinical benefit in a per-protocol (PP) analysis.

In this group, the 60-day mortality rate was 16% in the SCD-treated group compared to 41% in the control group.

Furthermore, the composite endpoint of mortality and/or dialysis dependency at day 60 was lower in the PP SCD-treated group compared to the control group (16% vs.

58%, respectively, p = 0.01) (Tumlin JA, et al.

2015;10(8):e0132482).

See additional details below on the SCD-003 study

To determine safety and efficacy of SCD therapy + CKRT in pediatric patients

Day 60 survival and 60-day dialysis dependency

75% of patients (12/16) survived to hospital discharge.

100% of surviving patients (12/12) were dialysis independent by day 60 (Goldstein SL, et al.

Kidney Int Rep .

2020;6(3):775-784;

Goldstein SL, et al.

Kidney Medicine.

https://doi.org/10.1016/j.xkme.2024.100).

See additional details below on the SCD-PED studies.

To assess the safety of SCD in children with AKI weighing ≥10 kg and ≤20 kg

5/6 (83%) patients survived to ICU discharge and all surviving patients were dialysis-independent by day 60 (Goldstein SL, et al.

Kidney Medicine.

https://doi.org/10.1016/j.xkme.2024.100).

See additional details below on the SCD-PED studies.

To assess the safety and efficacy of SCD in AKI or ARDS patients associated with COVID-19 infections

Mortality at day 60;

dialysis dependency at day 60;

ventilation at day 28

AKI or ARDS after COVID-19

SCD-treated patients had a reduction in 60-day mortality of 50% (11/22), vs 81% (13/16) in a contemporary control group from a concurrent prospective CKRT registry ( P =0.102).

The subjects who received >96 hours of SCD treatment, per protocol, had a further reduction in mortality to 31% (5/16) ( P <0.012) (Yessayan LT, et al.

Crit Care Explor .

2022;4(5):e0694).

Additional Details

SCD-003 was a controlled, randomized, and multicenter clinical trial that was initiated in September 2011 and terminated in September 2013 under an FDA approved IDE.

For this trial, the control group received standard CRRT with RCA and the SCD-treated group received up to seven days of SCD therapy.

The study was sponsored by SeaStar Medical with the support of a third-party contract research organization.

The study was sponsored by the Predecessor with the support of a third-party contract research organization.

The primary objective of the study was to determine if the SCD, when used in conjunction with CRRT, results in clinical and statistical improvement in mortality rate based on all causes through Day 60.

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Each participating clinical site used their established RCA protocol for the CRRT + SCD circuits (treatment group) and for the CRRT only (control group).

The recommended calcium (iCal) level (measured post SCD) in the CRRT

and SCD blood circuit was specified to be between 0.25 and 0.4 mmol/L.

The recommended calcium (iCal) level (measured post SCD) in the CRRT and SCD blood circuit was specified to be between 0.25 and 0.4 mmol/L.

Inclusion and exclusion criteria were similar to the previous IDE multicenter pilot clinical study except for an age range of 8-80 years and body weight of over 135 kilograms.

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During the second quarter of the enrollment period, a national calcium shortage occurred in the United States due to certain FDA-related quality manufacturing issues at major U.S.

Due to the reliance of the SCD on a narrow intra-circuit iCa range for functional efficacy and the concern that patients randomized to the SCD were not receiving effective therapy due to insufficient iCa levels, the interim analysis was performed early after enrollment of 134 patients.

Due to the reliance of the SCD on a narrow intra-circuit iCal range for functional efficacy and the concern that patients randomized to the SCD were not receiving effective therapy due to insufficient iCal levels, the interim analysis was performed early, after enrollment of 134 patients.

Enrollment was paused on May 24, 2013, to assess the clinical impact of the calcium shortage on study endpoints.

The shortage of calcium infusion solutions resulted in a tendency to minimize citrate infusion rates.

Accordingly, the iCa levels within the blood circuit tended to be above the recommended range of 0.25 to 0.40 mmol/L.

Accordingly, the iCal levels within the blood circuit tended to be above the recommended range of 0.25 to 0.40 mmol/L.

No significant differences were noted between the control and treatment groups in terms of baseline characteristics.

Of the 134 patients in the analysis, 69 received CRRT alone and 65 received SCD therapy.

Of the 134 patients in the analysis, 69 received CRRT alone and 65 received CRRT + SCD therapy.

No statistically significant difference was found between the treated and control patients with a 60-day mortality of 39% (27/69) and 36% (21/59), respectively.

No statistically significant difference was found between the SAEs of the control and treatment groups.

Furthermore, none of the SAEs were considered ‘definitely’

device related per the principal investigator.

The amount of time patients in both the control and treatment group were maintained in the recommended iCa range (0.23 - 0.40 mmol/L), as specified in the study protocol, was substantially lower than expected.

Of the 134 patients enrolled in the SCD-003 protocol at the time of the interim analysis, 19 SCD patients (CRRT + SCD) and 31 control patients (CRRT alone) were maintained in the protocol’s recommended range for greater or equal to 90% of the therapy time.

Furthermore, none of the SAEs were considered ‘definitely’ device related per the principal investigator.

The amount of time patients in both the control and treatment group were maintained in the recommended iCal range (0.23 - 0.40 mmol/L), as specified in the study protocol, was substantially lower than expected.

Of the 134 patients enrolled in the SCD-003 protocol at the time of the interim analysis, 19 SCD patients

(CRRT + SCD) and 31 control patients (CRRT alone) were maintained in the protocol’s recommended range for greater or equal to 90% of the therapy time.

The study was subsequently terminated.

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The most frequent categories of SAEs were infections and infestations as well as cardiac, respiratory, thoracic and mediastinal disorders.

Furthermore, none of the SAEs were considered “definitely”

related to the SCD device per the principal investigator.

Furthermore, none of the SAEs were considered “definitely” related to the SCD device per the principal investigator.

Overall adverse events did not differ between the treatment and control groups in the intent to treat analysis.

The following table lists all SAEs encountered during the study by category and the assessment of each SAE:

Study Related

List of Serious Adverse Events

Definitely Not

Blood and lymphatic system disorders

Cardiac Disorders

Gastrointestinal Disorders

General disorders and administration site conditions

Infections and infestations

Injury, poisoning and procedural complications

Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders

Nervous system disorders

Renal and Urinary Disorders

Respiratory, thoracic and mediastinal disorders

Vascular Disorders

When the iCa treated and control subgroups were compared for a composite index of 60-day mortality and dialysis dependency, the percentage of the SCD treated subjects was 16% versus 58% in the control subjects.

Among the per-protocol (PP) cohort of patients who achieved the recommended iCal range, the composite of death or dialysis dependency at 60 days was observed in 16% of SCD treated subjects versus 58% of control subjects.

The incidence of serious adverse events did not differ between the treated and control groups.

A new IDE was FDA approved on February 12, 2014 for a pivotal trial of 122 patients in up to 30 sites utilizing this primary composite endpoint.

If this trial met safety and effectiveness criteria, the FDA stated that a premarket approval and clearance was supportable.

This clinical trial was not initiated in 2014 due to continuing injectable calcium shortages, and the company limited the clinical focus to the pediatric indications, where less calcium was needed due to size of study (pediatric study had 15% of the patients compared to pivotal trial of 122 patients).

Safety and early efficacy trial of our SCD therapy in pediatric patients with AKI requiring CRRT (December 2016 and February 2020)

A multi-center, prospective pilot study was undertaken to assess the safety and efficacy of our SCD in pediatric patients with AKI being treated with continuous kidney replacement therapy with RCA.

SCD-PED-01 and 02 Studies – Additional Details

A multi-center, prospective pilot study SCD-PED-01 was undertaken to assess the safety and efficacy of our SCD in pediatric patients with AKI (weighing at least 20 kg) being treated with continuous kidney replacement therapy with RCA.

The primary objective of the study was to evaluate the safety of up to seven consecutive 24-hour treatments of our SCD.

The secondary objective was to evaluate the efficacy of up to seven consecutive 24-hour SCD treatments on all-cause mortality and dialysis dependency at Day 28 and Day 60.

This study was sponsored by SeaStar Medical with the support of a third-party contract research organization.

This study was sponsored by the Predecessor with the support of a third-party contract research organization.

Sixteen patients (eight male and eight female) were enrolled in the study at four United States pediatric medical centers, which ran from December 2016 through February 2020.

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None of the SAEs were device related.

There were 47 adverse events that occurred in 14 subjects in the study.

The following table lists all SAEs encountered during the study by category and the assessment of each SAE:

Study Related

List of Serious Adverse Events

Definitely Not

Cardiac Disorders

Gastrointestinal Disorders

Infections and infestations

Metabolism and nutrition disorders

Nervous system disorders

Renal and Urinary Disorders

Respiratory, thoracic and mediastinal disorders

Surgical and medical procedures

Vascular Disorders

A Multi-Center Pilot Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients Developing AKI or Acute Respiratory Distress Syndrome Associated with COVID-19

(September 2020 to July 2021).

Critical Care Exploration

Twenty-two subjects were enrolled in this pilot study at two leading medical centers.

All enrolled patients were treated with corticosteroids, either dexamethasone or hydrocortisone.

The majority of enrolled patients also received remdesivir.

Sixteen patients were included in the contemporaneous control.

Sixteen of the intent to treat (“ITT”) patients received greater than 96 hours of our SCD treatment per protocol (“PP”) since the inclusion criteria required

an intent to treat for at least 96 hours.

This study was sponsored by SeaStar Medical with the support of a third-party contract research organization.

The mortality rate of the ITT group at 60 days post-initiation of our SCD treatment was 50% and was 31% for the PP group.

The control group had a mortality rate of 81%, which was higher than both the ITT and PP treated groups.

The patients in the control group on Extracorporeal Membrane Oxygenation treatment did not survive, while 44% survived in the ITT group.

For dialysis dependency at 60 days, 60% of the survivors had not recovered renal function in the ITT group;

however, a post-hoc follow up at 90 days demonstrated that only 30% of the survivors still required dialytic support.

Fifty SAEs occurred in 18 subjects.

Of note, 22 nosocomial and opportunistic infections were reported in 12 subjects during the entire 60-day follow-up period.

Sixteen of the 22 infections occurred after SCD treatment.

None of these SAEs were device-related as determined by the site clinical investigators and the independent safety review committee.

No RCA-related adverse events were observed with greater than 90% of measured circuit ionized calcium (iCa) values less than 0.4 mmol/L.

Systemic iCa values were within the normal ranges required by the clinical protocol.

Two circuit clotting events were reported;

clotting was initiated in the hemodialysis catheter in one instance and in the hemofilter in the other.

No SCD clotting episodes were reported.

No episodes of thrombocytopenia, neutropenia, or leukopenia were observed.

The following table lists all SAEs encountered during the study by category and the assessment of each SAE:

Study Related

List of Serious Adverse Events

Definitely Not

Blood and lymphatic system disorders

Cardiac Disorders

Gastrointestinal Disorders

General disorders and administration site conditions

Hepatobiliary disorders

Infections and infestations

Injury, poisoning and procedural complications

Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders

Nervous system disorders

Renal and Urinary Disorders

Respiratory, thoracic and mediastinal disorders

Vascular Disorders

SeaStar Medical and the principal investigators of SCD-005 COVID-19 clinical study have recently been accepted and were recently published in Critical Care Exploration;

a peer reviewed academic journal.

Chronic Applications

Pilot Feasibility Trial of SCD Therapy in ESRD Patients (May 2012 to April 2013)

Our SCD therapy was evaluated in a more stable end stage renal disease (“ESRD”) patient cohort on chronic hemodialysis.

Fifteen ESRD patients were enrolled to assess the safety and early efficacy signals on inflammatory biomarkers.

Our SCD therapy promoted a monocyte shift from predominant proinflammatory to reparative phenotype.

Very few adverse events or SAEs were observed during SCD treatment and RCA.

SCD treatment and RCA was associated with adverse events in four of the 13 patients.

The adverse events were comprised of one episode each of

fever, chills, headache, itching, coughing, dizziness, muscle cramps, nausea, vomiting, and chest pain.

These adverse events are frequently experienced by patients undergoing standard hemodialysis treatment.

No adverse events were definitively related to SCD therapy.

SCD treatment and heparin anticoagulation, however, resulted in symptomatic and biochemical events.

The initial two patients (Pt1 and Pt2) of this cohort, treated with SCD and heparin anticoagulation, demonstrated a large rise in C-reactive protein levels from 22 to 38 (Pt1) and 51–132 (Pt2) mg/L after four hours of SCD treatment.

C-reactive protein levels continued to be elevated at 93 (Pt1) and 147 (Pt2) mg/L on day 1 post-SCD treatment.

Because of these events, no further patients were recruited for SCD treatment and heparin anticoagulation.

The following table lists all SAEs encountered during the study by category and the assessment of each SAE:

Study Related

List of Serious Adverse Events

Definitely Not

General disorders and administration site conditions

Additional Indications with Preclinical Data

The initial research and translation of our SCD into clinical studies was targeted to treat the acute dysregulated systemic inflammation associated with AKI and MOF.

Due to the broad applications of immunomodulatory therapy, preclinical models were developed to evaluate the efficacy of our SCD to ameliorate single organ tissue injury.

A Multi-Center, Randomized, Controlled, Pivotal Study to Assess the Safety and Efficacy of A Selective Cytopheretic Device in Patients with Acute Kidney Injury (SCD-003 –

IDEG090189) (September 2011 to May 2013)

Clinical Studies

Additional Indications with Preclinical Data

The initial research and translation of our SCD into clinical studies was targeted to treat the acute dysregulated systemic inflammation associated with AKI and Multi Organ Failure.

Due to the broad applications of immunomodulatory therapy, preclinical models were developed to evaluate the efficacy of our SCD to ameliorate single organ tissue injury.

Chronic Inflammatory Disorders

Chronic Heart Failure

Prior preclinical and clinical evaluations of our SCD therapy have focused on acute inflammatory conditions related to organ dysfunction and failure.

Extensions of the immunomodulatory approach to improve organ dysfunction related to chronic inflammation would be transformative.

Over the past decade, a number of novel pharmacologic approaches have failed to prove clinical efficacy, accentuating the need to discover new, safe approaches to treat chronic heart failure (“CHF”).

In this regard, our SCD was evaluated in a preclinical model of CHF to dampen the cardio-depressant effects of the chronic proinflammatory state of CHF.

Chronic heart failure and acute decompensated heart failure have been increasingly recognized as associated with chronic systemic inflammation.

Monocytes have been identified as critical sources of systemic inflammation in CHF and may cause a decrease in cardiac myocyte contractility.

A similar study known as SCD-PED-02 was undertaken in pediatric patients weighing between 10 and 20 kg.

The study enrolled 6 patients (proposed maximum of up to 10 patients).

5/6 (83%) patients survived to ICU discharge and all surviving patients were dialysis-independent by Day 60.

A combined pooled analysis of both the PED-01 and PED-02 studies (N=22 total) demonstrated a survival rate of ~77% at Day 60 in pediatric patients weighing at least 10 kg.

This data was published in the journal Kidney Medicine in February 2024.

Chronic Applications in Inflammatory Disorders and Corresponding Studies at the University of Michigan (“UoM”)

We are evaluating the safety and efficacy of our SCD in preliminary clinical trials that may lead to applications for our SCD in additional patient populations.

The following are examples of our ongoing efforts to identify additional patient populations that may benefit from treatment with our SCD.

Pilot Feasibility Trial of SCD Therapy in ESRD Patients

The SCD therapy was evaluated in a cohort of 15 end-stage renal disease (ESRD) patients on chronic hemodialysis.

The therapy promoted a shift in monocytes from a predominantly proinflammatory to a reparative phenotype.

Adverse events or serious adverse events (SAEs) were minimal during SCD treatment and RCA, with four of the 13 patients experiencing adverse events.

None of these adverse events were definitively linked to SCD therapy.

Cardiorenal Syndrome

Cardiorenal syndrome (“CRS”) is a clinical disorder in which therapy to relieve the congestive symptoms of chronic heart failure is limited by a decline in renal function.

Up to one-third of patients with acute decompensated chronic heart failure present with this disorder;

this condition is increasing in incidence with an estimated one million hospital admissions annually in the United States.

Once hospitalized, these patients are treated with high dose intravenous diuretics to relieve the persistent congestion.

Once hospitalized, these patients are treated with a high dose of

intravenous diuretics to relieve persistent congestion.

The use of diuretics, however, frequently results in worsening renal function, progression of heart failure and death.

Immune dysregulation plays a key role in cardiorenal syndrome.

The CRS clinical trial at the UoM is a safety and efficacy dose escalation study in 10 patients that was designed to evaluate whether ultrafiltration therapy in CRS, a disease with a dismal prognosis and currently ineffective therapy, with SCD therapy will improve cardiac and renal (production of urine) functions.

In the study, an improvement of cardiac function is measured by the rate of ejection fraction, which is the percentage of blood leaving the heart each time it contracts.

An improvement of renal function is measured by serum creatinine and blood urine nitrogen (two common biomarkers to assess renal function) levels.

In addition, a variety of other biomarkers will also be measured.

One patient has been successfully treated with the SCD thus far in this study.

The effect of the SCD on cardiac function was recently demonstrated in a first-in-human case report of a 71-year-old male patient with cardiorenal syndrome including severe heart failure with reduced ejection fraction and was deemed ineligible for cardiac transplantation or LVAD due to worsening renal function (WRF) and right ventricular dysfunction.

The patient was treated with the SCD and effectively bridged to LVAD and demonstrated proof-of-concept for an innovative approach to the treatment of CRS using our device.

These initial results now provide important feasibility data for a follow-on study to undertake a controlled randomized clinical trial to evaluate the clinical efficacy of our SCD in CRS patients that have failed ultrafiltration therapy.

Based on this data, our SCD recently received BDD for CRS in October 2023.

These results were recently published in the journal PLoS One in April 2023 and an additional perspective article was published in the journal European Journal of Heart Failure in February 2024.

Hepatorenal Syndrome (HRS)

Hepatorenal syndrome is characterized by an abrupt deterioration of kidney function, driven by a hyperinflammatory process in patients with advanced liver cirrhosis, and is associated with an unacceptably high mortality.

Without treatment, the prognosis for patients with hepatorenal syndrome is poor with most dying within weeks of the onset of renal failure.

In fact, the mortality rate for patients with severe acute or chronic liver failure with four or more organ failures at 28 days is 100%.

Approximately 700,000 cases of hepatorenal syndrome are reported in the U.S.

In 2019 the economic burden for hepatorenal syndrome hospitalization was estimated at $4.2 billion.

The NCT04898010 study is an investigator-initiated pilot study to assess the safety and efficacy of the SCD in treating up to 10 ICU patients with AKI and HRS Type I.

The study aims to understand the effect of 7 days of treatment with the SCD on white blood cells in the bloodstream of patients with hepatorenal syndrome and its impact on blood circulation and kidney function.

Two patients with type 1 hepatorenal syndrome have been treated to date in this study.

Positive clinical outcomes were seen in both cases - one patient with hepatorenal syndrome due to acute alcoholic hepatitis was alive at day 90 after seven days of SCD treatment and undergoing liver transplantation evaluation, and the other patient with hepatorenal syndrome due to non-alcoholic steatohepatitis or NASH had a successful liver transplantation 6 days after SCD therapy ended.

This suggested a role of SCD immunomodulation to treat acute or chronic liver failure, regardless of the etiology, as a bridge to evaluation or successful intervention for liver transplantation.

Both of these cases were recently published in the American Society for Artificial Internal Organs Journal in August of this year (Yessayan et al., ASAIO J.

10.1097/MAT.0000000000002033).

This led to the FDA granting the SCD a BDD for HRS in October 2023.

Myocardial Ischemia in End-Stage Renal Disease Patients on Chronic Hemodialysis

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Novel interventions need to be identified and tested to ameliorate the high morbidity and mortality of myocardial disease in these patients.

Multiple hemodynamic and inflammatory factors contribute to the elevated risk of cardiac disease in the chronic hemodialysis patient populations.

Multiple hemodynamic and inflammatory factors contribute to the elevated risk of cardiac disease in chronic hemodialysis patient populations.

Hemodialysis treatment is associated with repetitive ischemic events, or myocardial stunning, and is identified with regional wall motion abnormalities on echocardiograms.

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Both acute and chronic inflammation and its cellular immunologic effector, the activated monocyte, are central to the accelerated cardiovascular disease in patients with chronic end-stage renal disease.

Studies at the University of Michigan

Cardiorenal Syndrome Clinical Trial

The CRS clinical trial is a safety and efficacy dose escalation study in 10 patients that was designed to evaluate whether ultrafiltration therapy in CRS, a disease with a dismal prognosis and currently ineffective therapy, with use of the SCD therapy will improve cardiac and renal (production of urine) functions.

In the study, an improvement of cardiac function is measured by the rate of ejection fraction, which is the percentage of blood leaving the heart each time it contracts.

An improvement of renal function is measured by the serum creatinine and blood urine nitrogen (two common biomarkers to assess renal function).

In addition, a variety of other biomarkers will also be measured.

The successful completion of this study is expected to demonstrate proof-of-concept for an innovative approach to the treatment of CRS.

Initial results will provide important feasibility data for a follow-on study to undertake a controlled randomized clinical trial to evaluate the clinical efficacy of our SCD in CRS patients that have failed ultrafiltration therapy.

Myocardial Ischemia in End-Stage Renal Disease Patients on Chronic Hemodialysis Clinical Trial

Pilot safety and efficacy study in 10 patients to evaluate the reduction in myocardial stunning events in hemodialysis patients.

The primary outcome will measure the change in regional wall abnormalities identified on an echocardiogram.

Initial results will provide important feasibility data for a follow-on study to undertake a controlled randomized clinical trial to evaluate the clinical efficacy of the SCD in myocardial stunning hemodialysis patients.

Clinical Study

Product Development

Our first generation SCD has been based upon the design of a synthetic hemofilter due to the reduced regulatory risk of an FDA approved polysulfone hollow fiber cartridge.

Second generation prototypes will include flat end caps to allow consistent implementation of the therapy, which we expect is more suitable as we scale up our operations.

We are currently evaluating altered configuration for differing clinical indication, so that pricing decisions can be made based upon unmet medical need and product specifications.

A pilot safety and efficacy study in 10 patients to evaluate the reduction in myocardial stunning events in hemodialysis patients is planned at the UoM.

The primary outcome is expected to measure the change in regional wall abnormalities identified on an echocardiogram.

Initial results are expected to provide important feasibility data for a

follow-on study to undertake a controlled randomized clinical trial to evaluate the clinical efficacy of our SCD in myocardial stunning hemodialysis patients.

We source critical components from vendors that have been approved and qualified through our vendor management program.

Fresenius Medical Care North America (“FMCNA”) is the current supplier of the filter used in our pediatric acute kidney injury indication.

In March 2022, we entered into a supply agreement (the “Supply Agreement”) with an FMCNA affiliate, Fresenius USA Marketing, Inc.

(“FUSA”), to supply certain filters at an agreed amount per case for use in our SCD product in our upcoming clinical trial and any additional clinical trials.

Fresenius Medical Care North America (“FMCNA”) is the current supplier of the filter used in our pediatric acute kidney injury indication.

In March 2022, we entered into a supply agreement (the “Supply Agreement”) with an FMCNA affiliate, Fresenius USA Marketing, Inc.

(“FUSA”), to supply certain filters at an agreed amount per case for use in our SCD product in our upcoming clinical trial and any additional clinical trials.

We may resell the filters as part of the SCD system in both an Emergency Use Authorization application as well as a future PMA-approved product.

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Either party may terminate the Supply Agreement for uncured material breach or for the insolvency of the other party.

Agreement invalid or illegal and the parties are not able to agree on mutually acceptable addendum to the Supply Agreement.

In addition, either party may terminate the Supply Agreement if in the reasonable opinion of legal counsel for either party, any future changes in federal or state law or regulations make any portion of the Supply Agreement invalid or illegal and the parties are not able to agree on mutually acceptable addendum to the Supply Agreement.

We have agreed to indemnify FUSA against certain third-party claims.

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In addition, we have secured a supplier to provide the tubing set required to assemble the SCD device, although we are able to identify and secure additional sources of supplies for the tubing set as it is readily available in the market.

The Supply Agreement contains a provision granting FUSA a first right of refusal for the first three years after regulatory approval of our SCD product candidate to distribute the pediatric and adult products in the United States.

If during such period, SeaStar Medical elects to promote and sell the SCD through distributors, SeaStar Medical will be required to provide FUSA with a right of first refusal to be SeaStar Medical’s exclusive distributor of the SCD in the United States and its territories, provided that the SCD is not promoted or sold in a manner that is incompatible with any devices manufactured and/or sold by FUSA or its affiliates.

The Supply Agreement contains a provision granting FUSA a right of first refusal for the first three years after regulatory approval of our SCD product candidate to distribute the pediatric and adult products in the United States.

On December 27, 2022, we entered into a license and distribution agreement with Nuwellis.

We appointed Nuwellis as our exclusive distributor for the sale and distribution of SCD product throughout the United States once we receive written authorization from the FDA to market our SCD for pediatric use pursuant to our HDE application.

Third-Party Reimbursement

We anticipate that coverage and reimbursement by Centers for Medicare and Medicaid Services (" CMS") and private payors will be essential for most patients and health care providers to afford our treatments, particularly in the applications of continuous renal replacement therapy for dialysis access and the treatment of hyperinflammatory conditions, including AKI.

We anticipate that coverage and reimbursement by Centers for Medicare and Medicaid Services ("CMS") and private payors will be essential for most patients and health care providers to pay for our treatments, particularly in the applications of continuous renal replacement therapy for dialysis access and the treatment of hyperinflammatory conditions, including AKI.

Accordingly, future sales of our products will depend substantially, both domestically and abroad, on reimbursement by government authorities, private health coverage insurers and other third-party payors.

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It is difficult to predict what CMS will decide with respect to coverage and reimbursement for fundamentally novel products.

Risk Factors —

Risks Related to the Company’s Business Operations —

Should the Company’s products be approved for commercialization, lack of third-party coverage and reimbursement for the Company’s devices could delay or limit their adoption .”

See “ Risk Factors — Risks Related to the Company’s Business Operations — Should the Company’s

products be approved for commercialization, lack of third-party coverage and reimbursement for the Company’s devices could delay or limit their adoption .”

Intellectual Property

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In most countries in which we file, the patent term is 20 years from the earliest date of filing a non-provisional patent application.

In the United States, a patent’s term may be lengthened by patent term adjustment, which

compensates a patentee for administrative delays by the U.S.

In the United States, 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 in granting a patent.

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The Company also has 22 issued foreign patents and has 3 pending foreign patent applications.

The Company’s issued patents begin to expire in 2028, with the last of these patents expiring in 2034, although terminal disclaimers, patent term extension or patent term adjustment can shorten or lengthen the patent term.

The following table summarizes the number of our patents and patent applications as of December 31, 2023:

Granted Patents

Pending Applications

SCD Technology (Patent Families 1-5)

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These patents will expire from 2028-2031, and the pending application, if granted, will expire in 2028, assuming that the required maintenance fees are paid.

We also co-own with UOM counterpart patents granted in Canada, Japan and New Zealand, and one patent application pending in Europe.

These counterpart patents, and applications, if granted, will expire in 2028, assuming that the required maintenance fees are paid.

We also co-own with UOM counterpart patents granted in Canada, Japan and New Zealand.

These counterpart patents will expire in 2028, assuming that the required maintenance fees are paid.

The patents and applications in Patent Family 1 are as follows:

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United States

Systems for treating leukocytes and platelets and methods

for treating subject having inflammatory conditions by

processing leukocytes or platelets

Systems for treating leukocytes and platelets and methods for treating subject having inflammatory conditions by processing leukocytes or platelets

Systems and methods for processing leukocytes and

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A device for processing activated leukocytes

Systems and methods for processing leukocytes and

platelets and for treating inflammatory conditions

A device that processes platelets or leukocytes

Systems and methods for processing leukocytes and platelets and for treating inflammatory conditions

Expiration date if application is granted.

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federal government funding and is subject to obligations under the Bayh-Dole Act.

Pursuant to a license agreement with UOM (as amended, the “UOM License Agreement”), UOM has granted us a worldwide, royalty bearing, exclusive license to their interest in the co-owned patents and applications in Patent Family 1 in the field of medical devices for human therapeutics for certain technologies used in the SCD technology platform, including composition of matter and methods of use patents.

In consideration for such exclusive license, during the term of the UOM License Agreement, we agreed to pay UOM a royalty fee equal to 1% of net sales and reimbursement of patent costs.

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The UOM License Agreement also imposes certain diligence obligations on us and requires us to achieve specified milestone events by a certain date.

Under the UOM License Agreement, UOM’s liability is limited and we agreed to indemnify and hold UOM harmless in connection with the use of the licensed technology and activities related to the products created using such licensed patents and/or technology.

The UOM License Agreement will remain in effect, unless earlier terminated, until the latter of (i) the expiration of all licensed patents, (ii) the tenth anniversary of the Effective Date (as defined therein) or (iii) the seventh anniversary of the date of the First Commercial Sale (as defined therein).

Either party may terminate the UOM License Agreement for the other party’s material breach of any covenant or promise therein that remains uncured for 90 days.

We may also terminate the agreement by giving UOM 90-day advanced notice.

In addition to the co-owned patents and patent applications in Family 1, we also solely own four additional patent families (Families 2-5).

The UOM License Agreement will remain in effect, unless earlier terminated, until all licensed patents have expired.

If we materially breach the terms of the UOM License Agreement, UOM has a right to terminate the

In some cases, we may have an opportunity to cure a material breach within 30 days or 90 days, but in some cases UOM may terminate the agreement immediately upon our breach.

We may also terminate the agreement by giving UOM 90-day advanced notice provided certain conditions are met.

In addition to the co-owned patents and patent applications in Family 1, we also solely own four additional patent families (Families 2-5) directed to the SCD technology.

Patent Family 2 includes one U.S.

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The patent will expire in 2031, and the application, if granted, will expire in 2031, assuming that the required maintenance fees are paid.

Counterpart patents have been granted in Australia, Europe, and Japan with the European patent having been validated in France, Germany, Italy, Spain, and the United Kingdom, and a patent application is pending in

These patents, and the application, if granted, will expire in 2031, assuming that the required maintenance fees are paid.

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Cartridge for treating leukocytes or platelets and methods for treating a subject with an inflammatory condition

Germany, Italy,

France, Germany,

Italy, Spain, & UK

Cartridge for sequestering leukocytes or platelets

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Healthcare providers that use medical devices generally rely on third-party payors to pay for all or part of the costs and fees associated with the medical procedures being performed or to compensate them for their patient care services.

Lack of third-party coverage and reimbursement for the Company’s devices could delay or limit their adoption, and as such harm our competitive advantage in the market.

Sales and Marketing

While currently we do not have a significant sales and marketing capability, we are actively pursuing resources and support for commercialization efforts in anticipation of obtaining the relevant regulatory approval from the FDA, including for the HDE application for pediatric AKI indications that was submitted in June 2022.

While currently we do not have a significant sales and marketing capability, we are actively pursuing resources and support for commercialization efforts in light of obtaining FDA HDE approval for pediatrics with AKI on February.

On December 27, 2022, we entered into a U.S.

License and Distribution Agreement with Nuwellis, for the pediatric SCD that is under HDE review.

License and Distribution Agreement with Nuwellis, for the pediatric SCD that received approval on February 23, 2024.

On December 29, 2023, we amended the distribution and license agreement with Nuwellis.

We will leverage their existing sales team that has similar call points to those needed for the pediatric SCD.

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These agencies require manufacturers of medical devices to comply with applicable laws and regulations governing the development, testing, manufacturing, labeling, marketing, storage, distribution, advertising and promotion, and post-marketing surveillance reporting of medical devices.

The SCD includes a system of cartridges to interact with the patient’s hyperinflammatory cells to allow them to become deactivated prior to their return to the patient.

As the primary therapeutic mode of action of our SCD is attributable to the device’s impact on these autologous cells and their timely return to patients, FDA’s Center for Biological Evaluation and Research has primary jurisdiction over its premarket development, review and approval of our SCD as a medical device.

The SCD includes a system of cartridges to interact with the patient’s hyperinflammatory cells to allow them to become deactivated prior to their return to the patient.

Failure to comply with applicable requirements may subject a device and/or its manufacturer to a variety of administrative sanctions, such as issuance of warning letters, import detentions, mandatory safety notifications, repair/replace/refund actions, or recalls, civil monetary penalties and/or judicial sanctions, such as product seizures, injunctions and criminal prosecution.

FDA’s Pre-market Clearance and Approval Requirements

Each medical device we seek to commercially distribute in the United States will require either a prior 510(k) clearance, unless it is exempt, a de novo request or a PMA from the FDA.

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otherwise, a de novo or PMA is required.

Medical devices are classified into one of three classes—Class I, Class II or Class III—depending on the degree of risk associated with each medical device and the extent of control needed to provide reasonable assurance of safety and effectiveness.

Class I devices are deemed to be low risk and are subject to the general controls of the Federal Food, Drug, and Cosmetic Act ("FD&C Act"), such as provisions that relate to:

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By definition, rare diseases or conditions occur in a small number of patients.

As a result, it has

been difficult to gather enough clinical evidence to meet the FDA standard of reasonable assurance of safety and effectiveness.

As a result, it has been difficult to gather enough clinical evidence to meet the FDA standard of reasonable assurance of safety and effectiveness.

In order to address this challenge, Congress included a provision in the Safe Medical Devices Act of 1990 to create a new regulatory pathway for products intended for diseases or conditions that affect small (i.e., rare) populations, which is the Human Device Exemption program.

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HDE holders who wish to sell their devices for profit and who did not submit the request in the original HDE application may submit a supplement and provide adequate supporting documentation to demonstrate that the HUD meets the eligibility criteria.

The number of HDE devices that may be sold for profit is limited to a quantity known as the Annual Distribution Number (“ADN”).

If the FDA determines that an HDE holder is eligible to sell the device for profit, the FDA will determine the ADN and notify the HDE holder.

The ADN is calculated by taking the number of devices reasonably necessary to treat or diagnose an individual per year and multiplying it by 8000.

For example, if the typical course of treatment using an HDE device, in accordance with its intended use, requires the use of two devices per patient per year, then the ADN for that HDE device would be 16,000 (i.e., 2 x 8000).

For example, if the typical course of treatment using an HDE device, in accordance with its intended use, requires the use of seven devices per patient per year, then the ADN for that HDE device would be 56,000 (i.e., 7 x 8000).

If the number of devices distributed in a year exceeds the ADN, the sponsor can continue to sell the device but cannot earn a profit for the remainder of the year.

We believe our SCD will be eligible to sell for a profit because we are pursuing an HDE for the pediatric population.

The SCD (Quelimmune pediatrics) is eligible to sell for a profit as per the Final Approval Order issued to Company on February 23, 2024.

Pre-market Approval Pathway

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The pre-market approval application process is more extensive than the 510(k)-pre-market notification and de novo request processes.

A PMA application must be supported by extensive data, including but not limited to technical, preclinical, clinical trials, manufacturing and labeling to demonstrate to the FDA’s satisfaction reasonable evidence of safety and effectiveness of the device.

After a pre-market approval application is submitted, the FDA has 45 days to determine whether the application is sufficiently complete to permit a substantive review and thus whether the FDA will file the application for review.

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The total review process is highly variable and can take up to several years.

During this review period, the FDA may request

additional information or clarification of the information already provided.

During this review period, the FDA may request additional information or clarification of the information already provided.

Also, an advisory panel of experts from outside the FDA may be convened to review and evaluate the application and provide recommendations to the FDA as to the approvability of the device.

Although the FDA is not bound by the advisory panel decision, the panel’s recommendations are important to the FDA’s overall decision-making process.

In addition, the FDA generally conducts a preapproval inspection of the manufacturing facilities to ensure compliance with the Quality System Regulation (“QSR”).

The agency also may inspect one or more clinical sites to assure compliance with FDA’s regulations.

Although the FDA is not bound by the advisory panel decision, the panel’s recommendations are important to the FDA’s overall decision-making process.

In addition, the FDA generally conducts a preapproval inspection of the manufacturing facilities to ensure compliance with the Quality System Regulation (“QSR”).

The agency also may inspect one or more clinical sites to assure compliance with FDA’s regulations.

Upon completion of the PMA review, the FDA may:

(i) approve the PMA that authorizes commercial marketing with specific prescribing information for one or more indications, which can be more limited than those originally sought;

(ii) issue an approvable letter that indicates the FDA’s belief that the PMA is approvable and states what additional information the FDA requires, or the post-approval commitments that must be agreed to prior to approval;

(iii) issue a not approvable letter that outlines steps required for approval, but which are typically more onerous than those in an approvable letter, and may require additional clinical trials that are often expensive and time consuming and can delay approval for months or even years;

or (iv) deny the application.

If the FDA issues an approvable or not approvable letter, the applicant has 180 days to respond, after which the FDA’s review clock is reset.

Clinical Trials

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The IDE must be approved in advance by the FDA for a specific number of patients at specified study sites.

During the trial, the sponsor must comply with the FDA’s IDE requirements for investigator selection, trial monitoring, reporting and recordkeeping.

The investigators must obtain patient informed consent, rigorously follow the investigational plan and study protocol, control the disposition of investigational devices and comply with all reporting and recordkeeping requirements.

Clinical trials for significant risk devices may not begin until the IDE application is approved by the FDA and the appropriate institutional review boards (“IRBs”) at the clinical trial sites.

An IRB is an appropriately constituted group that has been formally designated to review and monitor medical research involving subjects and which has the authority to approve, require modifications in, or disapprove research to protect the rights, safety and welfare of human research subjects.

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• the QSR, which requires manufacturers, including third-party manufacturers, to follow stringent design, testing, control, documentation and other quality assurance procedures during all aspects of the manufacturing process;

labeling regulations and the FDA prohibitions against the promotion of products for uncleared, unapproved or “off-label”

uses and other requirements related to promotional activities;

• labeling regulations and the FDA prohibitions against the promotion of products for uncleared, unapproved or “off-label” uses and other requirements related to promotional activities;

• medical device reporting regulations, which require that manufactures report to the FDA if their device may have caused or contributed to a death or serious injury, or if their device malfunctioned and the device or a similar device marketed by the manufacturer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur;

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Supplements to a PMA often require the submission of the same type of information required for an original PMA, except that the supplement is generally limited to that information needed to support the proposed change from the device covered by the original PMA.

The FDA uses the same procedures and actions in reviewing PMA supplements as it does in reviewing original PMAs.

The FDA uses the same procedures and

actions in reviewing PMA supplements as it does in reviewing original PMAs.

PMA supplements also require the submission of a user fee, which varies depending on the type of supplement.

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The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including substantial monetary penalties and criminal prosecution.

Newly discovered or developed safety or effectiveness data may require changes to a product’s labeling, including the addition of new warnings and contraindications, and also may require the implementation of other risk management measures.

Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory clearance or approval of our products under development.

Healthcare Regulation

In addition to the FDA’s restrictions on marketing of pharmaceutical products, the United States healthcare laws and regulations that may affect our ability to operate include:

the federal fraud and abuse laws, including the federal anti-kickback and false claims laws, federal data privacy and security laws, and federal transparency laws related to payments and/or other transfers of value made to physicians and other healthcare professionals and teaching hospitals.

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Moreover, several states have enacted legislation requiring pharmaceutical manufacturers to, among other things, establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales and marketing activities, report information related to drug pricing, require the registration of sales representatives, and prohibit certain other sales and marketing practices.

These laws may adversely affect our

sales, marketing, and other activities with respect to any product candidate for which we receive approval to market in the United States by imposing administrative and compliance burdens on us.

These laws may adversely affect our sales, marketing, and other activities with respect to any product candidate for which we receive approval to market in the United States by imposing administrative and compliance burdens on us.

Because of the breadth of these laws and the narrowness of available statutory exceptions and regulatory safe harbors, it is possible that some of our business activities, particularly any sales and marketing activities after a product candidate has been approved for marketing in the United States, could be subject to legal challenge and enforcement actions.

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The Further Consolidated Appropriations Act, signed into law on December 20, 2019, has now permanently repealed the medical device excise tax.

In addition, the Budget Control Act of 2011, as amended by subsequent legislation, further reduces Medicare’s payments to providers by two percent through fiscal year 2027.

These reductions may reduce providers’

revenues or profits, which could affect their ability to purchase new technologies.

In addition, the Budget Control Act of 2011, as amended by subsequent legislation, further reduces Medicare’s payments to providers by two percent through fiscal year 2027.

These reductions may reduce providers’ revenues or profits, which could affect their ability to purchase new technologies.

Furthermore, the healthcare industry in the United States has experienced a trend toward cost containment as government and private insurers seek to control healthcare costs by imposing lower payment rates and negotiating reduced contract rates with service providers.

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The process involved in applying for coverage and reimbursement from CMS is lengthy and expensive.

Further, Medicare coverage is based on our ability to demonstrate that the treatment is “reasonable and necessary”

for Medicare beneficiaries.

Further, Medicare coverage is based on our ability to demonstrate that the treatment is “reasonable and necessary” for Medicare beneficiaries.

Even if products utilizing our technology receive FDA and other regulatory clearance or approval, they may not be granted coverage and reimbursement by any payor, including by CMS.

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None of our employees are represented by labor unions or covered by collective bargaining agreements.

Corporate History

The Company was initially incorporated as the Predecessor under the name Nephrion, Inc.

on June 6, 2007.

On August 3, 2007, we amended our corporate name to CytoPherx, Inc.

On June 19, 2019, we amended our corporate name to SeaStar Medical, Inc., herein the Predecessor as previously defined above.

On October 28, 2022, LMF Acquisition Opportunities, Inc.

( as defined above “LMF”), a Delaware special purpose acquisition company, consummated a series of transactions that resulted in the combination of LMF Merger Sub, Inc., a Delaware corporation and a wholly-owned subsidiary of LMF (“Merger Sub”), and the Predecessor, a Delaware corporation, pursuant to an Agreement and Plan of Merger, dated April 21, 2022 (the “Merger Agreement”), by and among LMF, Merger Sub and the Predecessor (the "Transaction").

Pursuant to the terms of the Merger Agreement, Merger Sub merged with and into the Predecessor, with the Predecessor surviving the merger as a

wholly-owned subsidiary of LMF (the “Business Combination”).

Following the consummation of the Business Combination, LMF was renamed “SeaStar Medical Holding Corporation” (the “Company”).

Available Information

We make available free of charge on or through our website, https://seastarmedical.com, our Annual Reports, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, proxy statements, and all amendments to those filings as soon as reasonably practicable after such material is electronically filed with, or furnished to, the Securities and Exchange Commission (“SEC”).

Information contained on our website is not incorporated by reference unless specifically stated therein.

Information contained on, or that may be accessed through our website is not part of, and is not incorporated into this Annual Report.

In addition, the SEC maintains a website that contains reports, proxy statements, and other information about issuers, such as us, who file electronically within the SEC.

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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