CRYO CELL INTERNATIONAL INC Management’s Discussion and Analysis of Financial Condition and Results of Operations. (form 10-Q) – Marketscreener.com

Forward Looking Statements

This Form 10Q, press releases and certain information provided periodically in writing or orally by the Company's officers or its agents may contain statements which constitute "forwardlooking statements". The terms "Cryo-Cell International, Inc.," "Cryo-Cell," "Company," "we," "our" and "us" refer to Cryo-Cell International, Inc. The words "expect," "anticipate," "believe," "goal," "strategy," "plan," "intend," "estimate" and similar expressions and variations thereof, if used, are intended to specifically identify forwardlooking statements. Those statements appear in a number of places in this Form 10Q and in other places, and include statements regarding the intent, belief or current expectations of the Company, its directors or its officers with respect to, among other things:

(i)

our future performance and operating results;

(ii)

our future operating plans;

(iii)

our liquidity and capital resources; and

(iv)

our financial condition, accounting policies and management judgments.

We have based these forward-looking statements on our current expectations, assumptions, estimates and projections. These forward-looking statements involve risks and uncertainties and reflect only our current views, expectations and assumptions with respect to future events and our future performance. If risks or uncertainties materialize or assumptions prove incorrect, actual results or events could differ materially from those expressed or implied by such forward-looking statements. The factors that might cause such differences include, among others:

(i)

any adverse effect or limitations caused by recent increases in government regulation of stem cell storage facilities;

(ii)

any increased competition in our business including increasing competition from public cord blood banks particularly in overseas markets but also in the U.S.;

(iii)

any decrease or slowdown in the number of people seeking to store umbilical cord blood stem cells or decrease in the number of people paying annual storage fees;

(iv)

any adverse impacts on revenue or operating margins due to the costs associated with increased growth in our business, including the possibility of unanticipated costs relating to the operation of our facility and costs relating to the commercial launch of new types of stem cells;

(v)

any unique risks posed by our international activities, including but not limited to local business laws or practices that diminish our affiliates' ability to effectively compete in their local markets;

(vi)

any technological or medical breakthroughs that would render our business of stem cell preservation obsolete;

(vii)

any material failure or malfunction in our storage facilities; or any natural disaster or act of terrorism that adversely affects stored specimens;

(viii)

any adverse results to our prospects, financial condition or reputation arising from any material failure or compromise of our information systems;

(ix)

the costs associated with defending or prosecuting litigation matters, particularly including litigation related to intellectual property, and any material adverse result from such matters;

(x)

the success of our licensing agreements and their ability to provide us with royalty fees;

(xi)

any difficulties and increased expense in enforcing our international licensing agreements;

(xii)

any adverse performance by or relations with any of our licensees;

(xiii)

any inability to enter into new licensing arrangements including arrangements with non-refundable upfront fees;

(xiv)

any inability to realize cost savings as a result of recent acquisitions;

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(xv)

any inability to realize a return on an investment;

(xvi)

any adverse impact on our revenues and operating margins as a result of discounting of our services in order to generate new business in tough economic times where consumers are selective with discretionary spending;

(xvii)

the success of our global expansion initiatives and product diversification;

(xviii)

our actual future ownership stake in future therapies emerging from our collaborative research partnerships;

(xix)

our ability to minimize our future costs related to R&D initiatives and collaborations and the success of such initiatives and collaborations;

(xx)

any inability to successfully identify and consummate strategic acquisitions;

(xxi)

any inability to realize benefits from any strategic acquisitions;

(xxii)

the Company's ability to realize a profit on the acquisition of PrepaCyte-CB;

(xxiii)

the Company's ability to realize a profit on the acquisition of Cord:Use;

(xxiv)

the impact of the COVID-19 pandemic on our sales, operations and supply chain;

(xxv)

the Company's actual future competitive position in stem cell innovation;

(xxvi)

future success of its core business and the competitive impact of public cord blood banking on the Company's business;

(xxvii)

the success of the Company's initiative to expand its core business units to include biopharmaceutical manufacturing and operating clinics, the uncertainty of profitability from its biopharmaceutical manufacturing and operating clinics, the Company's ability to minimize future costs to the Company related to R&D initiatives and collaborations and the success of such initiatives and collaborations and

(xxviii)

the other risk factors set forth in this Report under the heading "Risk Factors."

Readers are cautioned not to place undue reliance on these forward-looking statements, which reflect management's analysis only as of the date hereof. Cryo-Cell International, Inc. undertakes no obligation to publicly revise these forward-looking statements to reflect events or circumstances that arise after the date hereof. Readers should carefully review the risk factors described in other documents the Company files from time to time with the Securities and Exchange Commission.

Overview

The Company currently stores nearly 225,000 cord blood and cord tissue specimens for the exclusive benefit of newborn babies and possibly other members of their families. Founded in 1989, the Company was the world's first private cord blood bank to separate and store stem cells in 1992. The Company's U.S.-based business operations, including the processing and storage of specimens, are handled from its headquarters facility in Oldsmar, Florida.

Utilizing its infrastructure, experience and resources derived from its umbilical cord blood stem cell business, the Company has expanded its research and development activities to develop technologies related to stem cells harvested from sources beyond umbilical cord blood stem cells. In 2011, the Company introduced its new cord tissue service, which stores a section of the umbilical cord tissue. The Company offers the cord tissue service in combination with the umbilical cord blood service.

On February 23, 2021, the Company entered into a Patent and Technology License Agreement (the "Duke Agreement") with Duke University ("Duke"). The Duke Agreement grants the Company the rights to proprietary processes and regulatory data related to cord blood and cord tissue developed at Duke. The Company plans to explore, test, and/or administer these treatments to patients with osteoarthritis and with conditions for which there are limited U.S. Federal Drug Administration ("FDA") approved therapies, including cerebral palsy, autism, and multiple sclerosis. These treatments utilize the unique immunomodulatory and potential regenerative properties derived from cord blood and cord tissue. Pursuant to the Duke Agreement, the Company has been granted exclusive commercial rights to Duke's granted exclusive commercial rights to Duke's intellectual property assets, FDA regulatory data, clinical expertise and manufacturing protocols associated with various applications of cord blood and cord tissue stem cells. Through this Agreement, the Company intends to expand to a triad of core business units to include: (1) its cord blood bank and other storage services; (2) cord blood and cord tissue infusion clinic services initially under the FDA's Expanded Access Program and in conjunction with the undertaking of cord blood and cord tissue clinical trials to obtain biologics license application ("BLA") approvals for new indications, and (3) biopharmaceutical manufacturing if BLA(s) are approved by the FDA. The Company is projecting to open the Cryo-Cell Institute

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for Cellular Therapies and begin infusing patients with autologous cord blood units during the first quarter of 2023.

Cord Blood Stem Cell Processing and Storage Business

Background of Business

Nearly fifty years ago researchers discovered that cells could be cryopreserved at extremely low temperatures and all cellular activity would cease until the specimens were thawed. Historically, cryopreservation was required for organ transplants, blood banking and medical research. Today, cryopreservation of umbilical cord blood stem cells gives individuals the opportunity to potentially take advantage of evolving cellular therapies and other medical technologies.

Hematopoietic stem cells are the building blocks of our blood and immune systems. They form the white blood cells that fight infection, red blood cells that carry oxygen throughout the body and platelets that promote healing. These cells are found in bone marrow where they continue to generate cells throughout our lives. Stem cells can be stored in a cryogenic environment, and upon thawing, infused into a patient. They can be returned to the individual from whom they were taken (autologous) or donated to someone else (allogeneic). An individual's own bone marrow may be used for a transplant if the cancer has not entered the marrow system (metastasized). Otherwise, a marrow donor needs to be identified to provide the needed bone marrow. The availability of a marrow donor or matched stem cell specimen allows physicians to administer larger doses of chemotherapy or radiation in an effort to eradicate the disease. Stem cell therapies and transplants are used for both cancerous and non-cancerous diseases.

Stem cells are found in umbilical cord blood ("cord blood stem cells") and can be collected and stored after a baby is born. Over 40,000 cord blood stem cell transplants have been performed to date. The Company believes that many parents will want to save and store these cells for potential future use by their family, either for the donor or for another family member. Today, stem cell transplants are known and accepted treatments for at least 78 diseases, we believe, a number of them life-threatening. With continued research in this area of medical technology, other therapeutic uses for cord blood stem cells are being explored. Moreover, researchers believe they may be utilized in the future for treating diseases that currently have no cure.

It is the Company's mission to inform expectant parents and their prenatal care providers of the potential medical benefits from preserving stem cells and to provide them the means and processes for collection and storage of these cells. A vast majority of expectant parents are simply unaware that umbilical cord blood contains a rich supply of non-controversial stem cells and that they can be collected, processed and stored for the potential future use of the newborn and possibly related family members. A baby's stem cells are a perfect match for the baby throughout its life and have a 1-in-4 chance of being a perfect match and a 3-in-4 chance of being an acceptable match for a sibling. There is no assurance, however, that a perfect match means the cells could be used to treat certain diseases of the newborn or a relative. Today, it is still common for the cord blood (the blood remaining in the umbilical cord and placenta) to be discarded at the time of birth as medical waste.

Despite the potential benefits of umbilical cord blood stem cell preservation, the number of parents of newborns participating in stem cell preservation is still relatively small compared to the number of births (four million per annum) in the United States. Some reasons for this low level of market penetration are the misperception of the high cost of stem cell storage and a general lack of awareness of the benefits of stem cell preservation programs. However, evolving medical technology could significantly increase the utilization of the umbilical cord blood for transplantation and/or other types of treatments. The Company believes it offers the highest quality, highest value service targeted to a broad base of the market. We intend to maximize our growth potential through our superior quality, value-driven competitive leadership position, product differentiation, an embedded client base, increased public awareness and accelerated market penetration.

The Company believes that the market for cord blood stem cell preservation is enhanced by global discussion on stem cell research developments and the current focus on reducing prohibitive health care costs. With the increasing costs of bone marrow matches and transplants, a newborn's umbilical cord blood cells can be stored as a precautionary measure. Medical technology is constantly evolving which may provide new uses for cryopreserved cord blood stem cells.

Our Cord Blood Stem Cell Storage Services

The Company enters into storage agreements with its clients under which the Company charges a fee for the processing and testing and first year of storage of the umbilical cord blood. Thereafter, the client is charged an annual fee to store the specimen, unless the client entered into an 18-year pre-paid storage plan or a lifetime pre-paid storage plan.

The Company's corporate headquarters are located in a nearly 18,000 square-foot state-of-the-art current Good Manufacturing Practice and Good Tissue Practice (cGMP/cGTP)-compliant facility. Food and Drug Administration ("FDA") 21 CFR Part 1271, effective in May 2005, requires human cellular and tissue-based products to be manufactured in compliance with good tissue practices (cGTPs). In addition, the cellular products cryogenic storage area has been designed as a "bunker," with enhanced provisions for security,

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building fortification for environmental element protection and back-up systems for operational redundancies. The Company believes that it was the first private bank to process cord blood in a technologically and operationally advanced cGMP/cGTP-compliant facility. The Company's facility, which also currently houses the Company's client services, marketing and administrative operations, is designed to accommodate a broad range of events such as client tours and open houses, as well as educational workshops for clinicians and expectant parents.

Due to the limited storage capacity of its existing facility in Oldsmar, FL, the Company is currently seeking a new building to house its stored specimens. If this facility is purchased, the Company believes it will have space for not only its existing and future internal storage needs, but also will have the capacity to offer third party pharmaceutical companies and medical institutions storage services, to set up a cellular therapy laboratory to manufacture MSCs and possibly the space to consolidate the Cryo-Cell Institute for Cellular Therapies under the same roof in the future.

Competitive Advantages

The Company believes that it provides several key advantages over its competitors, including:

Cord Tissue

In August 2011, the Company introduced its advanced new cord tissue service, which stores a section of the umbilical cord tissue. Approximately six inches of the cord tissue is procured and transported to the Company's laboratory for processing, testing and cryopreservation for future potential use. Umbilical cord tissue is a rich source of MSCs, which have many unique functions including the ability to inhibit inflammation following tissue damage, to secrete growth factors that aid in tissue repair, and to differentiate into many cell types including neural cells, bone cells, fat cells and cartilage. MSCs are increasingly being researched in regenerative medicine for a wide range of conditions.

In June 2018, the Company acquired substantially all of the assets of Cord:Use Cord Blood Bank, Inc., a Florida corporation ("Cord:Use"), in accordance with the definitive Asset Purchase Agreement between Cryo-Cell and Cord:Use(the "Purchase Agreement"), including without limitation Cord:Use's cord blood operations and its inventory of public cord blood units existing as of the closing date (the "Public Cord Blood Inventory"), which included both public (PHS 351) and private (PHS 361) banks. The Company closed the Cord:Use location and maintains its operations in Oldsmar, Florida. The new PHS 351 product is distributed under an IND (10-CBA) maintained by the National Marrow Donor Program ("NMDP"). The Company has continued the contract with Duke initiated by Cord:Use to manufacture, test, cryopreserve, store and distribute the public cord blood units. As part of the Cord:Use Purchase Agreement, the Company has an agreement with Duke, expiring on January 31, 2025, for Duke to receive, process, and store cord blood units for the Public Cord Blood Bank ("Duke Services"). As of November 30, 2021, the Company had approximately 6,000 cord blood units in inventory. Costs charged by Duke for their Duke Services are based on a monthly fixed fee for processing and storing 12 blood units per month. The public units are listed on the NMDP Single Point of Access Registry and are available to transplant centers worldwide. The Company is reimbursed via cost recovery for public cord blood units distributed for transplant through the NMDP.

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Pursuant to the Purchase Agreement, Cord:Use is entitled to an earn out from the Company's sale of the Public Cord Blood Inventory from and after closing. Each calendar year after the closing, the Company is required to pay to Cord:Use 75% of all gross revenues, net of any returns, received from the sale of public cord blood inventory in excess of $500,000 up to an aggregate amount of $200,000,000. Such payments are to be made quarterly, within 30 days of the end of the last month of each calendar quarter, until the public cord blood inventory is exhausted. In addition, each calendar year after closing, until the public cord blood inventory is exhausted, for every $500,000 of retained gross revenues, net of any returns, received and retained by the Company in excess of the initial $500,000 retained by the Company during such year, the Company is also required to deliver its common stock to Cord:Use, up to an aggregate total value of $5,000,000. As of November 30, 2021, the Company has delivered 465,426 shares at $7.52 per share of its common stock to Cord:Use.

The Public Cord Blood Inventory creates a large, ethnically diverse, high-quality inventory of available cord blood stem cell units for those in need of life saving therapy. The Company collects cord blood units at hospitals in Florida, Arizona, California, Michigan and Washington. The Company's public inventory is stored at Duke in North Carolina, and the cord blood units are sold through the NMDP located in Minnesota, who ultimately distributes the cord blood units to transplant centers located in the United States, and around the world.

In connection with its acquisition of Cord:Use, the Company acquired 665,287 shares of Tianhe Stem Cell Biotechnologies, Inc., an Illinois corporation ("Tianhe"). We believe these shares represent approximately 5% of the Tianhe capital stock. In addition to the other amounts payable to Cord:Use, pursuant to the Cord:Use Asset Purchase Agreement, the Company agreed to pay Cord:Use (1) the Tianhe Sales Earnout; (2) the Tianhe Valuation Earnout; and (3) the Tianhe Recap Earnout (collectively hereinafter referred to as the "Earnout Payments"), which are further discussed below.

If the Company generates more than $500,000 in gross profits from the sale of the Tianhe capital stock (whether in a single transaction or series of transactions) (each, a "Tianhe Sale Event"), the Company is obligated to pay Cord:Use 7% of the gross profits derived from such sale in excess of $500,000 in gross profits (collectively, the "Eligible Profits"), payable in a number of shares of common stock of the Company (the "Tianhe Sales Earnout") equal to the quotient of the dollar amount of the Eligible Profits divided by the average of the closing sale prices of common stock during the 30 consecutive full trading days ending at the closing of trading on the trading day immediately prior to the date the Tianhe Sale Event. "Gross profit", for these purposes, means the gross sale price of each share of Tianhe Stock sold pursuant to the Tianhe Sales Event minus (x) 0.43 per share and (y) all reasonable and documented transaction expenses (paid to third parties) directly related to the sale of the Tianhe Stock.

In the event a Tianhe Sale Event has not occurred on or before the five year anniversary of the Closing Date of the Cord:Use Asset Purchase Agreement, then the Company and Cord:Use will select an independent valuator to determine the fair market value of the Tianhe Stock owned by the Company and the Company will pay Cord:Use the Tianhe Valuation Earnout, which is 7% of the gross profits that would have been derived from a hypothetical sale of Tainhe capital stock, provided, that, notwithstanding the foregoing, in the Company's sole discretion, the Company may, instead of issuing shares of its common stock, transfer 7% of its Tianhe Stock to Cord:Use in full payment of the Tianhe Valuation Earnout.

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CRYO CELL INTERNATIONAL INC Management's Discussion and Analysis of Financial Condition and Results of Operations. (form 10-Q) - Marketscreener.com

Creating an environment for research to thrive – Dal News – Dal News

To attract the worlds best researchers, Dalhousie must provide the tools and spaces they require to meet their goals. To build labs, purchase technical equipment and acquire leading-edge soft- and hardware, the university receives substantial support from the Canada Foundation for Innovations John R. Evans Leaders Fund and Research Nova Scotia, which together have contributed $3.7 million in new funding for infrastructure.

Great researchers need great facilities. The support of our funders helps ensure we have the leading-edge research environment necessary to continue recruiting and retaining top talent from around the globe, says Alice Aiken, Dal's vice-president research and innovation.

From new capabilities in nuclear magnetic resonance to the creation of dedicated spaces to conduct Indigenous research, Dalhousie is now set to empower its scholars to engage in some of the most sophisticated research in the world.

Read more about the scholars who are receiving infrastructure funding and the research they will pursue.

Understanding the signals that allow us to see

Dr. Agosto explores the mechanisms that allow our eyes to detect the world around us and transmit information to the brain. Through experiments in mice and cell culture models, she aims to understand which proteins are required for signal transmission between cells, how they get to the right location, and how they work together. She anticipates that this work will help future efforts to restore light sensitivity following the death of rods and cones that occurs as a consequence of inherited retinal degeneration diseases.

Creating a lab to analyse forced migration

The number of people displaced worldwideexceeds 84 million,with 2021 having the highest figures on record and growing with increasing speed. The International Migration Research Lab led by Dr. Banerjee responds to this challenge with technical capacity and methodological expertise to collect, analyze, and disseminate qualitative data on migration governance and refugee policy. Outfitted with transcription software and equipment, qualitative data analysis software, and focus-group and research collaboration facilities, the lab enables knowledge generation and mobilization at domestic and international levels.

Investigating why men are more likely to die of right heart failure

When patients have increased blood pressure in the lungs or diseases of the left side of the heart, the right ventricle is exposed to higher pressure that can lead to heart failure. Men are far more likely to die from this condition than women. Dr. Chaudhary will investigatehow right ventricles react differently to stressin males and females and study the mechanisms underlying differential blood vessel growth in female versus male right ventricles, focusing on the role of sex hormones and blood vessel stem cells. Using the knowledge he gains; he and his team will develop and test new treatment options for patients suffering from right heart failure.

Examining why inflammation leads to disease

The health consequences of unwanted inflammation have been known for many years in academic and public settings. Ideally, inflammation rapidly clears pathogens and damaged tissue to return tissues to their previous healthy state. However, chronic inflammation can lead to inflammatory bowel disease, heart disease, arthritis, and hyperinflammatory conditions, such as seen in septic and severe COVID-19 patients. Using critical scientific equipment, Dr. Fairn and his research team are working to understand better the mechanisms of inflammation and its contributions to disease.

Working to reduce inequalities in healthcare

Equity in health and healthcare has been a long-standing policy objective both within Canada and globally. Policymakers are challenged to reduce health inequities due to a limited understanding of how to effectively influence the social determinants of health. Dr. Hajizadehs research program will use cutting-edge interdisciplinary methods to examine socioeconomic inequalities in health and healthcare and their causes, as well as the effects of health and public policies on health and healthcare equity. The overall aim ofhisresearch program is to inform policymaking that reduces inequities in health and healthcare.

Building a research space to enhance Indigenous participation

Indigenized research spaces are important for research engaging with women and gender diverse persons and building linkages between Mikmaw and Indigenous peoples and academics, government, the community of Nova Scotia and beyond. Dr. Pictou will create the Lnuey Governance Research Centre (Lnuey Belonging to the Lnu the people) at Dalhousie to support her work examining a re-grounding of Indigenous women and governance based on Indigenous land-based laws and treaty relations. She will generate and apply a gender analysis from an Indigenous perspective to enhance Indigenous participation in governance and decision-making processes related to environmental and natural resource governance.

Leveraging nuclear magnetic resonance to improve health

Led by Dr. Rainey, this project will establish a biomolecular nuclear magnetic resonance spectroscopy facility at Dalhousie University. Dr. Rainey and his team will use the sophisticated equipment to understand how spider silk proteins can be modified to design new biomaterials that can be used as sutures or for regeneration of injured nerves. The equipment will also be used to study hormone-receptor systems with the aim of creating treatments and preventive measures for conditions such as cardiovascular disease, cancer, and viral infection.

Creating a Mikmaw Cultural Research Lab

Dr. Robinson will create a Mikmaw Cultural Research Lab to support community-engaged social science research immersed in Mi'kmaw culture and language. The research lab will conduct community-driven social science research with Indigenous people, using Indigenous methods and field-tested technology, and will support Indigenous data ownership control, access, and possession. The facility will provide a commitment to cultural safety and assert the space as part of Mi'kma'ki, reinforcing Indigenous belonging in educational spaces.

Harnessing mountain wetlands for water supply and carbon absorption

Because wetlands remain waterlogged year-round, plant matter in the soil is slow to decompose, making them globally important carbon sinks. However, the role of mountain wetlands in storing and releasing water and carbon is not well understood. Climate is changing more quickly in mountain regions which may be profoundly changing their ability to store carbon and water. Dr. Somers and her team aim to develop a new understanding of mountain wetlands to determine how best to manage or restore these important landscapes in the face of climate and land use change and to maximize their capacity to supply potable water and absorb atmospheric carbon.

Designing early interventions to reduce severe mental illness

Dr. Uher examines the development of mental health and tests interventions to reduce the risk of severe mental illness in young people. He and his research team have found that mental illness, and depression in particular, is predictable and may be preventable. He has shown that a mix of clinical interviews, speech analysis, sleep and brain measurements can identify risk and resilience and predict treatment outcomes. This funding will help young people participate in a one-stop assessment that provides accurate information about their health and indications for early personalised treatment.

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Creating an environment for research to thrive - Dal News - Dal News

FDA Grants Direct Biologics Regenerative Medicine Advanced Therapy (RMAT) Designation for the use of ExoFlo in COVID-19 Related ARDS USA – English -…

AUSTIN, Texas, April 13, 2022 /PRNewswire/ -- Direct Biologics, an innovative biotechnology company with a groundbreaking extracellular vesicle (EV) platform drug technology, announced that the U.S. Food and Drug Administration (FDA) has awarded their EV drug product ExoFlo with a Regenerative Medicine Advanced Therapy (RMAT) designation for the treatment of Acute Respiratory Distress Syndrome (ARDS) associated with COVID-19. The RMAT program is designed to expedite the approval of promising regenerative medical products in the US that demonstrate clinical evidence indicating the ability to address an unmet medical need for a serious life-threatening disease or condition. Under the RMAT designation, the FDA provides intensive guidance on drug development and post-market requirements through early and frequent interactions. Additionally, an RMAT confers eligibility for accelerated approval and priority review of biologics licensing applications (BLA).

"After intensively reviewing our preclinical data, manufacturing processes, and clinical data from our Phase II multicenter, double blinded, placebo controlled randomized clinical trial, the FDA has recognized ExoFlo as a lifesaving treatment for patients suffering from Acute Respiratory Distress Syndrome (ARDS) due to severe or critical COVID-19," said Mark Adams, Chief Executive Officer. "The additional attention, resources, and regulatory benefits provided by an RMAT designation demonstrate that the FDA views ExoFlo as a product that can significantly enhance the standard of care for the thousands still dying from ARDS every week in the US," he said.

"We are very pleased that the FDA has recognized the lifesaving potential of our platform drug technology ExoFlo. The RMAT has provided a pathway to expedite our drug development to achieve a BLA in the shortest possible time," said Joe Schmidt, President. "I am very proud of our team. Everyone has been working around the clock for years in our mission to save human lives taken by a disease that lacks treatment options, both in the US and abroad. We are grateful for the opportunity to accelerate development of ExoFlo under the RMAT designation as it leads us closer to our goal of bringing our life saving drug to patients who desperately need it."

ExoFlo is an acellular human bone marrow mesenchymal stem cell (MSC) derived extracellular vesicle (EV) product. These nanosized EVs deliver thousands of signals in the form of regulatory proteins, microRNA, and messenger RNA to cells in the body, harnessing the anti-inflammatory and regenerative properties of bone marrow MSCs without the cost, complexity and limitations of scalability associated with MSC transplantation. ExoFlo is produced using a proprietary EV platform technology by Direct Biologics, LLC.

Physicians can learn more and may request information on becoming a study site at clinicaltrials.gov. For more information on Direct Biologics and regenerative medicine, visit: https://directbiologics.com.

About Direct BiologicsDirect Biologics, LLC, is headquartered in Austin, Texas, with an R&D facility located at the University of California, and an Operations and Order Fulfillment Center located in San Antonio, Texas. Direct Biologics is a market-leading innovator and cGMP manufacturer of regenerative medical products, including a robust EV platform technology. Direct Biologics' management team holds extensive collective experience in biologics research, development, and commercialization, making the Company a leader in the evolving segment of next generation regenerative biotherapeutics. Direct Biologics has obtained and is pursuing multiple additional clinical indications for ExoFlo through the FDA's investigational new drug (IND) process. For more information visit http://www.directbiologics.com.

Photo - https://mma.prnewswire.com/media/1781269/Direct_biologics_Logo.jpg

SOURCE Direct Biologics

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FDA Grants Direct Biologics Regenerative Medicine Advanced Therapy (RMAT) Designation for the use of ExoFlo in COVID-19 Related ARDS USA - English -...

Research Efforts Seek to Further Explore the Potential of Uproleselan in AML – OncLive

The addition of the E-selectin antagonist uproleselan (GMI-1271) to chemotherapy has been shown to improve outcomes in patients with relapsed/refractory acute myeloid leukemia (AML), according to Tapan M. Kadia, MD, who added that based on these findings, the investigative agent is now under further exploration in several disease subsets and settings with varying unmet need.

The idea is that [uproleselan] may reduce or subvert chemotherapy resistance. This has been shown in several preclinical studies where mice that had been treated with cytarabine and had leukemic blasts left over after [treatment] showed that they had tight binding to E-selectin within the tumor microenvironment, Kadia explained. When uproleselan, or an antibody blocking E-selectin, was added, those cells then became sensitive to the cytarabine, suggesting that the E-selectin binding was leading to chemotherapy resistance. This [supported the hypothesis that] blocking E-selectin within the microenvironment can be an important mechanism to provide benefit in patients with AML.

Data from a phase 1/2 clinical trial (NCT02306291) showed that when uproleselan was administered at the recommended phase 2 dose of 10 mg/kg twice daily in combination with mitoxantrone, etoposide, and cytarabine (MEC), it produced a remission rate of 41% in those with relapsed/refractory disease (n = 47).1 In a cohort of patients with newly diagnosed disease who were at least 60 years of age (n = 25), the combination of uproleselan plus cytarabine and idarubicin (7+3) resulted in a remission rate of 72%.

Now, a phase 3 trial (NCT03616470) is examining MEC or fludarabine, cytarabine, and idarubicin (FAI) with or without uproleselan in patients with relapsed/refractory AML who are eligible for intensive chemotherapy in the salvage setting.2 Another phase 3 trial (NCT03701308) is exploring 7+3 chemotherapy with or without uproleselan in patients aged 60 years or older who are fit for intensive induction chemotherapy.3 Moreover, a phase 1/2 trial (NCT04848974) is evaluating cladribine and low-dose cytarabine in combination with uproleselan in difficult-to-treat patients with treated secondary AML.4

In an interview with OncLive, Kadia, an associateprofessor in the Department of Leukemia, of the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed what makes uproleselan unique from other agents under investigation in AML and shed light on the many research efforts dedicated to further exploring its use in this disease.

Kadia: E-selectin is a relatively new target, but it is a protein that we have known about for many years. E-selectin is present on activated endothelial cells, [which are] the cells that make up a blood vessel. E-selectin is present, upregulated, and overexpressed in activated endothelial cells at the sites of inflammation and damage.

We [believe] E-selectin is meant to help attract or traffic leukocytes and white blood cells, including monocytes, neutrophils, and natural killer [NK] cells, to the sites of inflammation. Neutrophils, NK cells, and monocytes have E-selectin ligands, which are glycoproteins that are attracted to or attached to E-selectin. E-selectin on the endothelial cells helps to traffic these cells and adhere them to the endothelial cells.

More recently, E-selectin has become recognized as a potentially important marker in malignancy, because they are also expressed in endothelial cells associated with malignancy. For example, in solid tumors, there is a suggestion that it may have a role in metastasis or distant metastasis of solid tumors, such as colon cancer.

In leukemia and hematologic malignancies, the endothelial cells in bone marrow also overexpress E-selectin, particularly in advanced disease. They are expressed at higher levels in patients who have adverse-risk AML, patients who have been previously treated, and they allow the adherence of leukemic blasts of the malignant cells to the endothelial microenvironment within the bone marrow.

As [the endothelial cells do that], we believe that the E-selectin binding to these cells upregulates nuclear factor kappa B [NF-B] within the tumor or the blast, and elicits a type of chemotherapy resistance, or prosurvival pathways, that allow them to survive chemotherapy or treatment. Blocking this [from happening] has been the rationale behind [the development of] uproleselan. Blocking this may help prevent the trafficking of the blast cells to the bone marrow and from adhering to the bone marrow microenvironment, therefore inhibiting activation of the cancer survival pathways, such as NF-B.

Uproleselan is an antagonist of E-selectin that binds to E-selectin and prevents the interaction between E-selectin and E-selectin ligands, which are present on leukemia or AML blasts. It is an intravenous product that is given over 20 minutes twice daily.

[During] an initial study, [investigators] observed no significant toxicities [with uproleselan] as a single agent. The mechanism is that it blocks the interaction between the E-selectin and the E-selectin ligands on the blasts, therefore reducing the trafficking of these leukemic blasts to the bone marrow. It disrupts the adhesion-mediated drug resistance within the bone marrow microenvironment.

In that respect, it also inhibits the activation of potential cancer survival mechanisms, such as upregulation of NF-B, and may reduce chemotherapy-based toxicity that may occur. By reducing [E-selectin adhesion] and adding chemotherapy, you are treating cells that are potentially more sensitive to [chemotherapy].

The [hypothesis] was that blocking E-selectin would thereby sensitize the resistant leukemic blasts to chemotherapy, particularly in the salvage setting. You want to start in patients with relapsed/refractory AML.

This was a phase 1 study that looked at the combination of the E-selectin antagonist, uproleselan, with either MEC chemotherapy in patients with relapsed/refractory AML, or in combination with 7+3 chemotherapy in a small cohort of newly diagnosed patients with AML who were aged 60 years and older. Once patients achieved remission, they could also get uproleselan with their consolidation, whether it be MEC consolidation or intermediate-dose cytarabine-based consolidation.

A total of 66 patients with relapsed/refractory AML were treated, with a median age of 59 years of age. Moreover, 17% of those patients had prior transplant, and one-third of the patients had 2 or more induction regimens; [as such, it was] a heavily pretreated population. Fifty percent of patients had adverse-risk [disease] by European LeukemiaNet risk [classification].

If you look at the adverse [effects (AEs)], and this is 1 of the first striking observations, there may have been potentially lower toxicityparticularly along the gastrointestinal tract starting with mucositis, nausea, and vomitingthan what you would expect with MEC chemotherapy based on historical experience. The most common complications were infections, which are common in patients [with leukemia] who are treated with intensive chemotherapy.

When you look at efficacy among the 66 patients who were treated, the complete response [CR]/CR with incomplete count recovery [CRi] rate was [41%], and the early mortality [rate] was fairly low, at 9% at 60 days, which is reasonable. Patients who had a longer CR1 duration had a higher response rate at 75% vs those who had refractory disease or a short CR1 duration, [with] response rates in the range of 23% and 36%.

[Additionally], 69% of patients had minimal residual disease [MRD] negativity, which is good for a relapsed/refractory cohort setting. The efficacy was there, as seen by the overall response rate [ORR] of 39%, which is in line with what you would expect with salvage chemotherapy in the relapsed/refractory setting. The median overall survival [OS] of the patients is [8.8] months, [which is] promising for a study looking at relapsed/refractory AML.

One of the interesting correlative studies looked at E-selectin ligand expression on the blast cells and survival. Looking at baseline AML, a prior study suggested that patients whose blasts had high expression of E-selectin ligand had a more adverse prognosis then those with low expression. Moreover, E-selectin ligand overexpression [is known to] correlate with relapsed/refractory disease and adverse prognosis disease. As such, high E-selectin ligand is associated with a poor prognosis.

[However, in this correlative study,] patients who had high E-selectin ligand expression and were treated with uproleselan had a more favorable outcome, with a median OS of 12.7 months compared with 5.2 months in those who had low [E-selectin ligand] expression. That suggests that in those patients who typically would have a more adverse prognosis with high E-selectin ligand expression, when you added uproleselan, which blocked that interaction, their prognosis improved. That was an early signal that suggested that targeting that receptor flips the adverse prognosis associated with E-selectin ligand expression.

[The phase 1/2] study also had an arm of newly diagnosed patients, who were treated with 7+3 chemotherapy plus [uproleselan]. These were older patients with newly diagnosed AML; [this cohort was comprised of] 25 patients who had a median age of 67 years. Half of patients had secondary AML, which is commonly seen in that population.

Here, the rates of grade 3 or 4 mucositis were 0%, with about 20% [of patients experiencing] grade 1/2 mucositis, so lower rates in mucositis than we may have expected with intensive chemotherapy. The CR/CRi rate was 72% [with this approach], with 52% [of patients] achieving a complete remission. The early mortality [rate] at 60 days was 12%, [which is] higher than you might expect in older patients, but still reasonable and promising. The MRD negativity [rate] was 56% among the patients who were evaluated for it. As such, this was a pretty good response rate that was in line or higher than what you would expect with intensive chemotherapy.

Based on the promising data from the phase 1 trial, looking at patients with relapsed/refractory AML treated with MEC plus uproleselan, as well as the small cohort of frontline patients treated with uproleselan and 7+3, the sponsor decided to proceed with a couple of phase 3 randomized trials to register uproleselan for patients in these particular settings.

The primary end point for both studies is OS, to evaluate the combination of anti-leukemic activity uproleselan with the respective chemotherapy. Secondary end points also include trying to further study and nail down the incidence of severe oral mucositis. Is it less than what you would expect with the control arm?

The first is a randomized phase 3 study [NCT03616470] for patients between the ages of 18 years and 75 years, with relapsed/refractory AML who are eligible for intensive chemotherapy in the salvage setting. They may have had 1 or fewer allogeneic stem cell transplants [ASCTs] prior to enrollment. Patients are randomized [1:1] to either MEC or FAI chemotherapy, plus or minus uproleselan. If patients achieved remission, they could receive consolidation with high-dose [cytarabine] or intermediate-dose [cytarabine], plus or minus uproleselan. The primary end point of the study is OS. The study is in the early stages [and we] hope to see data in the next couple of years.

The second is an National Cancer Institute study [NCT03701308] that is looking at patients aged 60 years or older who are fit for intensive chemotherapy [in the frontline setting]. Patients who have secondary AML [will be included], but those with FLT3-mutated AML [will not], since there is a standard of care for that [in the form of] FLT3 inhibitors.

Here, patients are randomized [1:1] to 7+3 chemotherapy with or without uproleselan, with consolidation with intermediate-dose cytarabine, with or without uproleselan. The primary end point [is] OS, and there will be an interim analysis looking at event-free survival [EFS]. If there is an inferior EFS at the interim [analysis], then the study would be closed at that point for futility. Otherwise, it would continue to look for OS benefit [with this approach]. Hopefully, we will see some data in the next year or 2 [to shed light on whether] this is a good strategy [for these pateints].

The treatment paradigm in AML has shifted significantly over the past few years with the incorporation of new molecules, such as venetoclax [Venclexta], [plus] IDH1, IDH2, and FLT3 inhibitors. Things are changing rapidly, even as uproleselan is being developed.

Now, instead of saying we have patients who are older and fit for chemotherapy, you must ask [questions about mutations]. Does a patient have a FLT3 mutation? If so, maybe they should be treated with a FLT3 inhibitor combined with chemotherapy. Does a patient have an IDH1 or IDH2 mutation? Recent data from the 2021 ASH Annual Meeting suggested that the combination of ivosidenib [Tibsovo] and azacitidine showed a significant survival benefit in patients who are IDH1 mutated compared with azacitidine alone. As such, there is another option for that specific subset of patients.

We have other medications or intensive chemotherapy for patients who have secondary AML. [For example,] CPX-351 showed a significant survival benefit compared with 7+3 chemotherapy. Where does uproleselan fit in secondary AML? Well, if you start with the relapsed/refractory setting, there is no 1 standard of care. As such, if uproleselan does show significant benefit compared with MEC alone in terms of survival, that is one place to go.

[If patients] have FLT3-, IDH1-, or IDH2-mutated, options such as gilteritinib [Xospata] and ivosidenib are available for those respective subtypes. However, in those patients who do not have those mutations, [uproleselan] could be an option.

A [phase 1/2] pilot study [NCT03214562] that is being done by [investigators at The University of MD Anderson Cancer Center] looked at [the combination of] FLAG [fludarabine, cytarabine, granulocyte colonystimulating factor] plus idarubicin and venetoclax [in patients with relapsed/refractory AML] and showed very high rates of complete remission with MRD negativity. This is a very intensive study, that needs close follow-up and close safety evaluation, but certainly, [we are seeing] high response rates with most of the patients able to proceed to ASCT and good survival in the long term. How does uproleselan fit in that setting?

If [the addition of uproleselan] shows a benefit over MEC as a single agent, it is certainly an option. [Now, we must determine] which patients you would put on that particular study, if they have no targetable mutations or if they cannot tolerate intensive chemotherapy plus venetoclax, whether it be FLAG plus idarubicin/venetoclax, or a regimen we developed, [like CPX-351] plus venetoclax.

In the frontline setting, it gets even more difficult because frontline studies are looking at [combining] a hypomethylating agent [HMA] with venetoclax in older patients. This [approach] is currently approved for patients who are aged 75 and older, or those who are unfit for intensive chemotherapy. However, [this approach] may start to be applied to patients who are slightly younger than that or who are more fit than the most unfit patients. [Investigators] are examining HMA plus venetoclax in that older, fit population. New regimens, such as cladribine, low-dose cytarabine, plus venetoclax, have also demonstrated high response rates in that older, fit population.

A set of studies is evaluating [CTX-351 in secondary AML]. For patients with IDH1 mutations, we now have the option of HMA plus ivosidenib. For FLT3-mutated disease, we are still looking, but HMA/venetoclax has high response rates in that setting. Moreover, triplet combinations are also being investigated, where [agents such as] gilteritinib or quizartinib are being added to the backbone of HMA plus venetoclax.

In the frontline, so many different options [are available] for specific subtypes, so we must define where 7+3 plus uproleselan will fit in, if data are positive. This is still a question that will need to be answered.

We are conducting a trial in a specific subset of patients who do not have great options [available to them] right now: those with treated secondary AML. This is a population of patients who may have had myelodysplastic syndrome [MDS] or chronic myelomonocytic leukemia [CMML] prior to developing AML, which is very common in the population. These patients were treated with the standard of care, which is HMAs and 5-azacytidine or decitabine in the frontline for MDS or CMML.

Eventually, these patients may respond [to treatment], but they may then progress to AML. At the time of their progression, they are considered to have newly diagnosed AML, but they may have received months or years of HMAs. This [scenario] used to be [referred to as] HMA failure, but this is a specific subset of AML that arises from previously treated MDS or CMML. In these patients, the complete remission rates are in the range of 20% to 25% with standard agents, and early mortality is very high. These patients have a median OS in the range of 4 to 5 months at the time of diagnosis AML, so it is a difficult subset of patients [to treat] for whom there really is no therapy [available]. If you look at CPX-351 in that setting, which is treated secondary AML, outcomes are pretty much the same, with high rates of early mortality and poor OS.

We wanted to address this key subset of patients. One of the things that we learned from the preclinical studies with uproleselan is that E-selectin is upregulated and overexpressed in AML blasts that have been previously exposed to HMAs. AML or MDS blasts that have been treated with or exposed to HMAs upregulate E-selectin significantly. The rationale was if these patients who have failed or have been treated extensively with HMAs then develop AML, their blasts may have upregulated E-selectin, and they may be the ideal target for uproleselan in combination with chemotherapy.

We took that specific subset of patients, and we are studying the combination of uproleselan plus cladribine and low-dose cytarabine [as part of a phase 1/2 trial (NCT04848974)]. The cladribine and low-dose cytarabine regimen has been developed at MD Anderson and, for many years now, has been used in frontline AML and treated secondary AML. In that specific subset [of treated secondary AML], we have seen a response rate [ranging from] 35% to 40% in the frontline [setting].

Since it is not [additional treatment with a] HMA, this backbone in combination with uproleselan is being studied in patients with treated secondary AML, with the end point of safety, [as well as] secondary end points of remission rate and OS in this difficult population, where there is a [need] that needs to be critically addressed.

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Research Efforts Seek to Further Explore the Potential of Uproleselan in AML - OncLive