Direct Biologics Reports Compelling Results From Phase 2 Trial With ExoFlo™ in Hospitalized Patients With Respiratory Failure or Moderate-to-Severe Acute Respiratory Distress Syndrome (ARDS) Due to COVID-19

Relative risk reduction in mortality of 61.6% at Day 60 reported among ExoFlo-15 mL patients

Significant improvement in 60-day mortality in patients aged 18-65 with COVID-19 induced respiratory failure treated with ExoFlo

Randomized, controlled Phase 3 registrational trial is currently enrolling patients with COVID-19 induced moderate-to-severe ARDS

AUSTIN, Texas–(BUSINESS WIRE)–Direct Biologics, LLC, a late-stage biotechnology company leveraging its regenerative medicine platform using extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) to address multiple disease indications, announced favorable safety, dosing and efficacy results from its Phase 2 clinical trial of ExoFlo™ in hospitalized adult COVID-19 patients with moderate-to-severe acute respiratory distress syndrome (ARDS).

ExoFlo™ is designed to leverage the anti-inflammatory, immunomodulatory and regenerative properties of bone marrow MSC-derived EVs. In March 2022, the U.S. Food and Drug Administration (FDA) awarded ExoFlo a Regenerative Medicine Advanced Therapy (RMAT) designation for the treatment of severe or critical COVID-19.

“We are pleased to report compelling findings that provide hope to the thousands of patients around the world with respiratory failure and moderate-to-severe ARDS due to COVID-19. ExoFlo is the first regenerative medicine product candidate to demonstrate a significant survival benefit while being well-tolerated in a randomized, controlled clinical trial in patients with respiratory failure and ARDS,” said Mark Adams, Chief Executive Officer of Direct Biologics. “The potential for ExoFlo to treat patients with ARDS represents an advancement in efforts to reduce morbidity and mortality caused by the serious inflammatory complications of COVID-19.”

“Results from our randomized Phase 2 trial demonstrate that ExoFlo was well tolerated, as well as activity related to mortality and other key clinical indicators that track the need for hospitalization and ICU-level patient care. Findings demonstrated a significant survival benefit in ExoFlo-treated patients with respiratory failure due to COVID-19. We look forward to further studying ExoFlo in this indication through EXTINGUISH COVID-19, our pivotal Phase 3 trial, which is actively enrolling patients,” said Joe Schmidt, President of Direct Biologics. “In addition to the ongoing Phase 3 trial, the FDA authorized an expanded access trial of ExoFlo for the treatment of more severe pulmonary complications and critically ill patients with COVID-19 that do not meet inclusion criteria for the pivotal Phase 3 EXTINGUISH COVID-19 trial.”

Phase 2 Trial Design

From September 2020 through May 2021, Direct Biologics conducted a multicenter, double-blind, randomized, placebo-controlled Phase 2 trial of intravenous ExoFlo in hospitalized COVID-19 patients with moderate-to-severe ARDS as determined by modified Berlin criteria. A total of 102 adult patients were randomized 1:1:1 to receive a 60-minute infusion of (1) ExoFlo-15 mL diluted to 100 mL in normal saline, (2) ExoFlo-10 mL diluted to 100 mL in normal saline or (3) placebo, followed by a repeat infusion 72 hours later if the patient did not recover. Aside from ExoFlo, all patients, including those receiving placebo, received standard of care treatment for severe-to-critical COVID-19. The trial’s primary endpoint was 7-day change in partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio. Secondary endpoints included 60-day mortality rate, ventilator-free days (VFDs), time to hospital discharge and incidence of serious adverse events (SAEs).

Phase 2 Safety and Clinical Efficacy Results

All 102 patients enrolled were evaluated for adverse events (AEs) and SAEs. On review by an independent data safety monitoring board (DSMB), no AEs or SAEs were determined to be related to ExoFlo. No infusion reactions were observed. No difference in the incidence of AEs or SAEs, or in the distribution of types of AEs was observed between treatment arms (n=24, ExoFlo-15 mL; n=26, ExoFlo-10 mL; n=23, control). Treatment-emergent adverse events (TEAEs) that led to death were lower in ExoFlo-15 mL (n=10) than in ExoFlo-10 (n=13) and control (n=16).

The 60-day overall mortality rate was 47.1% in the placebo arm and 29.4% in the ExoFlo-15 mL arm, yielding a 17.7% absolute and a 37.6% relative risk reduction in mortality among patients who received ExoFlo-15 mL. When separating out patients aged 18-65 with respiratory failure, there was a statistically significant decreased mortality in the ExoFlo-15 group compared with placebo with an absolute and relative risk reduction of 30.8% and 61.6%, respectively. In patients aged 18-65 with ARDS, a decreased absolute and relative risk reduction in mortality of 41.9% and 57.7%, respectively, was observed. Given the statistically significant decrease in 60-day mortality observed in patients aged 18-65, this was chosen as the primary endpoint for the pivotal Phase 3 clinical trial.

Additional efficacy endpoints demonstrated a significant reduction in VFDs among patients who received ExoFlo 15 mL aged 18-65 with respiratory failure compared with placebo, and an improvement in time to hospital discharge and PaO2/FiO2 ratios. As not all endpoints were powered to reach statistical significance, further evaluation is being performed with larger patient numbers in the ongoing Phase 3 clinical trial.

“It is truly exciting to see a regenerative medicine product candidate achieve a significant survival benefit in COVID-19 patients with respiratory failure. As we enroll patients in our global, multisite, pivotal Phase 3 trial, I am encouraged by the potential ExoFlo holds to treat pulmonary complications including ARDS. We eagerly await these results and look forward to reviewing the data from this Phase 3 trial,” said Amy Lightner, M.D., Chief Medical Officer of Direct Biologics.

Regulatory Discussions and Further Study

The FDA has granted Direct Biologics an allowance to proceed with a Phase 3 trial of ExoFlo-15 mL compared with placebo, randomized 1:1. This multisite global trial will look at 60-day all-cause mortality in patients who meet Berlin criteria for moderate-to-severe ARDS. The trial is powered to confirm a mortality benefit and will concurrently examine secondary endpoints including VFDs, oxygen-free days and time to hospital discharge, among others, to evaluate the ability of ExoFlo to reduce patient morbidity and mortality in the context of severe and critical COVID-19.

About Direct Biologics

Direct Biologics is a late-stage biotechnology company leveraging a regenerative medicine platform which uses extracellular vesicles (EVs) secreted from mesenchymal stem cells to address multiple disease indications. Direct Biologics’ mission is to be the global leader in regenerative medicine through discovery, innovation, advancement of science, and treatment of patients in a safe and effective manner. Our therapeutic product candidate, ExoFlo, is designed to be a scalable, reproducible, and effective next-generation biologic that leverages our proprietary EV platform technology designed to reduce inflammation, modulate the immune system, and restore tissue through cellular regeneration. Direct Biologics is currently conducting the global Phase 3 EXTINGUISH COVID-19 clinical trial of ExoFlo for the treatment of hospitalized COVID-19 adults with moderate-to-severe acute respiratory distress syndrome (ARDS). In addition, the Company has initiated Phase 1 clinical trials with ExoFlo for the treatment of ulcerative colitis and Crohn’s disease, and expanded access trials in solid abdominal organ transplantation, and severe COVID-19 ARDS patients. Direct Biologics intends to pursue additional clinical applications including all-cause ARDS, perianal fistulizing Crohn’s disease, and necrotizing enterocolitis. Headquartered in Austin, Texas, Direct Biologics also has an R&D facility at the Center for Novel Therapeutics on the campus of University of California at San Diego, and operations and order-fulfillment center in San Antonio, Texas. For more information, please visit www.directbiologics.com and follow us on Twitter @directbiologics.

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