COVID-19 and other Viral Induced ARDS

Recent clinical and epidemiological data confirms that the primary cause of serious or critical illness, and the most frequent cause of death following COVID-19 infection is acute respiratory distress syndrome (ARDS), which can be induced by the virus. While many individuals will recover from viral infection after experiencing only mild to modest symptoms, a range of viral pathogens can induce severe pulmonary inflammation in patients, including SARS, MERS, virulent influenza (e.g., H1N1), and COVID-19. When the lungs become inflamed they accumulate fluid, a process referred to clinically as edema, and the lung tissue becomes structurally abnormal. This results in lung function becoming significantly compromised, preventing normal oxygenation, and resulting in serious or critical illness as well as death in some patients.

Unfortunately, there is no FDA approved and effective medicine for ARDS. The current standard of care is to place patients on a ventilator, which forces oxygen into the lungs to keep the patient alive. Unfortunately, given the current limitations in standard of care, the morbidity and mortality from ARDS is high, especially among older patients and patients with underlying health issues or co-morbid conditions. Patients with ARDS that are ventilated for an extended period of time and survive frequently experience long term pulmonary damage due to ventilator induced fibrosis and scarring, and also experience compromised quality of life.

Currently MultiStem is the only investigational cell therapy that has shown promise for the treatment of ARDS that has been granted both Fast Track and RMAT designation by the FDA.

MACOVIA Study (MultiStem Administration for COVID-19 Induced ARDS)

We are currently enrolling a Pivotal Phase 2/3 clinical trial evaluating MultiStem cell therapy in COVID-19 induced ARDS patients. This trial is a multicenter study with an open-label, single active treatment arm for cohort 1 followed by a double-blind, randomized, placebo-controlled Phase 2/3 portion. The primary objectives of the MACOVIA study are to evaluate the safety and efficacy of MultiStem therapy as a treatment for subjects with moderate to severe ARDS due to COVID-19.

The primary efficacy endpoint will be an evaluation of ventilator-free days through day 28 as compared to placebo, a well-established endpoint for ARDS trials that evaluates an intervention’s combined impact on survival and liberation from invasive mechanical ventilation. The secondary objectives of this study include evaluation of pulmonary function, all-cause mortality, time in intensive care, hospitalization, tolerability and quality of life (QoL) among survivors associated with MultiStem therapy as a treatment for subjects with moderate to severe ARDS due to COVID-19.

The study is designed to enroll approximately 400 subjects and will be conducted at leading pulmonary critical care centers throughout the United States.

The Completed Phase 1/2 (MUST-ARDS) Study

In May 2019 we presented positive results from a randomized, double blind, placebo controlled exploratory clinical study evaluating MultiStem cell therapy for treatment of ARDS at the American Thoracic Society Meeting in Dallas. ARDS is a serious immunological and inflammatory condition characterized by widespread inflammation in the lungs. ARDS can be triggered by pneumonia, sepsis, or trauma and represents a major cause of morbidity and mortality in the critical care setting. It has significant implications, as it prolongs intensive care unit (ICU) and hospital stays and requires convalescence in the hospital and rehabilitation.

Patients in the exploratory study were evaluated through 28 days for the primary clinical assessment and were further assessed through a one-year follow-up period. We announced the encouraging one year data in January of 2020. Data highlights from the trial include the following:

Lower mortality of 25% in the MultiStem treatment group vs. 40% in the placebo group;

40.2% higher ventilator-free (VF) days, (12.9 VF days in the MultiStem treatment group vs. 9.2 VF days for the placebo group);

27.2% higher ICU-free days, (10.3 days in MultiStem subjects vs. 8.1 days for subjects receiving placebo);

Rapid improvement in pulmonary function was observed among MultiStem treated subjects, with 45% of these patients achieving ventilator independence by study day 7 vs only 20% placebo in the placebo group;

In more severe ARDS patients (as evident from a prospectively defined analysis), the difference between MultiStem treatment and placebo was greater – 25% mortality in MultiStem group vs. 50% in placebo group, 14.6 VF days in MultiStem group vs. 8.0 VF days in placebo group, and 11.4 ICU-free days in MultiStem group versus 5.9 ICU-free days in placebo group;

Day-365 Quality of Life (QoL) outcomes, assessed by the EQ-5D, were meaningfully better among all survivors who received MultiStem treatment compared to those who received placebo;

Within the prospectively defined group of patients with more severe ARDS, MultiStem treatment was associated with a markedly greater rate of survival and progression to functional independence at one year (i.e., self-care); and

MultiStem treatment was well tolerated in this very sick ARDS patient population, with no serious adverse events related to administration.

Primary Endpoints:

Safety and tolerability within 4 hours of MultiStem therapy administration;

Suspected Unexpected Serious Adverse Reactions (SUSARs) within 24 hours of MultiStem therapy administration.

Conclusion: The primary endpoints were met.

These primary endpoints were assessed by the following procedures:

Subjects were monitored post-administration for infusion-related reactions. Vital signs including blood pressure, pulse, respiration, pulse oximetry and temperature were collected.

We evaluated for all adverse events, paying special attention to the following:

- Sustained hypoxemia, of more than 30 minutes, related to the infusion of the investigational product

- Sustained hypotension, of more than 30 minutes, related to the infusion of the investigational product

- New cardiac arrhythmia related to the infusion of the investigational product requiring cardioversion

- New ventricular tachycardia, ventricular fibrillation or asystole related to the infusion of the

investigational product.

Conclusion: The primary endpoints were met; MultiStem was well tolerated throughout the 4-hour observation period described above and no adverse events of special interest occurred. There were no SAEs throughout the one-year study causally related to MultiStem investigational therapy.

The study was designed to evaluate the impact of MultiStem treatment in subjects with acute onset of moderate to severe ARDS and was conducted at sites in the United States and United Kingdom. The study included two parts – a small initial dose confirmation phase, followed by the larger double blinded, placebo-controlled and randomized phase (Phase 2a portion). Treatment was required to begin within four days of ARDS diagnosis with an average treatment time of approximately two days from the diagnosis. Six subjects were treated with MultiStem in the initial portion of the study, and in the Phase 2a portion of the study, 20 subjects were treated with an intravenous (IV) administration of 900 million MultiStem cells and 10 subjects received IV placebo. As disclosed previously, the study was not powered for the efficacy outcomes. Based on the study results, the Company is planning further development in this area and intends to submit for publication the detailed study data.

In May 2019 we announced that our ARDS program received Fast Track Designation from the FDA, based on the promising data from the Phase 1/2 study and the potential to treat this area of unmet medical need. In September 2020 we announced that the program has also received RMAT designation. In addition, our partner HEALIOS K.K. is currently running the ONE-BRIDGE study using MultiStem cell therapy, and they anticipate completing enrollment by the end of 2020. On November 14, 2019, HEALIOS K.K. received notification of Orphan Designation for their ARDS program, which is meant to expedite the regulatory process for development and provides other meaningful benefits.

There are limited interventions and no effective drug treatments for ARDS, making it an area of high unmet clinical need with high treatment costs. Given ARDS high treatment costs, a successful cell therapy could be expected to generate significant savings for the healthcare system by reducing days on a ventilator, days in the ICU and total days in the hospital, and importantly, could reduce mortality and improve quality of life for those suffering from the condition. The medical need for a safe and effective treatment of ARDS is significant due to its high mortality rate, and it annually affects approximately 400,000 - 500,000 patients in Europe, the United States and Japan, alone.

After undergoing a thorough review, BARDA and the CoronaWatch task force has designated MultiStem as a “Highly Relevant” therapeutic for COVID-19. Our near-term priorities are to negotiate and secure external funding to support the MACOVIA study (e.g., BARDA, NIH, other governmental institutions).



Links to Resources and Relevant Company News

The ARDS Foundation - ARDS Foundation is a nonprofit organization dedicated to supporting patients and families faced with the horrific diagnosis of Acute Respiratory Distress Syndrome (ARDS)

9/11/2020: Spectrum News 1 - Cleveland-based Athersys holding COVID-19 stem cell therapy clinical trials (Video)

7/27/2020: BioWorld - Potential COVID-19 cell therapy treatments in development

7/10/2020: Cell & Gene Therapy Insights (Podcast) - Regulatory affairs in regen med: building trust, expediting development and navigating the impact of COVID-19

6/4/2020: Cell Culture Dish (Podcast) - Multistem – A Stable, Off-the Shelf Regenerative Medicine Has Demonstrated Promise in Treating Patients with Acute Respiratory Distress Syndrome or ARDS

5/21/2020: Alliance for Regenerative Medicine Webinar - Dr. Eric Jenkins, Sr. Medical Director and Head of Clinical Operations, Athersys, discusses our ARDS program

5/6/2020: BioWorld - Pass the MUST-ARDS: Athersys starts pivotal study for stem cells to treat COVID-19-induced ARDS

5/4/2020: WOIO News - University Hospitals and Cleveland biotech company Athersys team up for COVID-19 clinical trial

5/1/2020: WKYC News - University Hospitals beginning coronavirus therapy trial

5/1/2020: Crain's Cleveland Business - UH Cleveland Medical Center will be the first clinical site for a new Athersys Inc. trial

5/1/2020: Cleveland.com - University Hospitals is first clinical site for MultiStem cell therapy study to combat coronavirus-induced ARDS

4/1/2020: Fox News and "America's Newsroom" - Cell Therapy Touted as Possible Coronavirus Treatment by Cleveland Biotech

3/26/2020: 90.3 WCPN Ideastream - Cleveland Company Testing Possible Therapy For Deadly COVID-19 Complication

3/26/2020: GEN Edge - Athersys Stem Cell Therapy Targets Top Cause of COVID-19 Deaths

3/25/2020: NBC News - Tracking the Development of Coronavirus Treatment

3/25/2020: RegMedNet - 'Highly Relevant' Cell Therapy for Acute Corona-related Respiratory Distress

3/23/2020: WKYC Cleveland News - Cleveland Biotech Company Making Headway on Possible COVID-19 Treatment (Video)