Direct Biologics’ Phase 1 Clinical Trial Seeks to Treat Crohn Disease With Extracellular Vesicles


In observance of Crohn and Colitis Awareness Week, observed from December 1 to 7, CGTLive™ took a closer look at the clinical evaluation of the MSC-derived therapy, ExoFlo.

Direct Biologics’ ExoFlo, an investigational therapy composed of extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs), is currently being evaluated in a phase 1 clinical trial (NCT05130983) for the treatment of medically refractory Crohn disease (CD).1 In observance of Crohn and Colitis Awareness Week, observed from December 1 to 7, 2023, by the patient and clinician communities, CGTLive™ decided to take a closer look at this ongoing study.

The trial, led by study director Amy Lightner, MD, the chief medical officer of Direct Biologics, was initiated with the dosing of the first participant in March 2023. The open-label, multicenter study is expected to take place over the course of 24 months, with each patient individually participating for 58 weeks. The investigators seek to enroll 10 participants in total. According to the page, which was last updated on September 1, 2023, the study is still actively recruiting. Participants in the trial will receive ExoFlo intravenously across 15 separate doses. Initially, participants will receive 15 mL doses on days 0, 2, and 4 of the study. Going forward, participants will be treated with 30 mL doses given at weeks 2 and 6; from there, the patients will continue to receive 30 mL doses every 4 weeks until they reach week 46.

The trial is taking place at centers in Los Angeles, California, and New York, New York. In Los Angeles, Phillip R. Fleshner, MD, the director of Colorectal Surgery Research at Cedars-Sinai, is serving as the principal investigator. In New York, David P. Hudesman, MD, the codirector of the NYU Langone Inflammatory Bowel Disease Center, serves as the principal investigator. As of September 2023, both sites were actively recruiting patients.

Although the study includes exploratory efficacy end points, it is primarily focused on establishing safety and is not powered to demonstrate the efficacy of ExoFlo in this populaiton. The primary end points are safety as assessed by the occurrence of serious adverse events (AEs) and treatment-related AEs and feasibility as assessed by whether 4 or more participants are incapable of receiving ExoFlo. Secondary end points will assess the ability of ExoFlo to cause clinical remission or a clinical response at weeks 6 and 46; response and remission are defined by sufficient decreases from baseline in CD Activity Index score (CDAI). The Simple Endoscopic Score for Crohn Disease (SES-CD), Short Form Health Survey, and the EuroQoL 5 Dimensions Survey will additionally be used to further evaluate efficacy.

Beyond efficacy, changes in C-reactive protein and fecal calprotectin will be used to determine pharmacokinetics and pharmacodynamics. The study will count as treatment failure cases of disease worsening, need for rescue medications or surgical intervention for CD, or discontinuation of participation because of treatment-related AEs.

The study is open to patients aged 18 to 75 years of age who have had Crohn colitis lasting a minimum of 6 months and whose disease symptoms did not improve after treatment with 1 or more monoclonal antibodies taken for 8 weeks. Patients who are intolerant to monoclonal antibody treatments may also participate, as can patients who have a contraindication for monoclonal antibody treatments and would otherwise need to undergo heightened medical management or a subtotal colectomy. Patients' CD must be medically refractory according to CDAI or SES-CD score.

Meanwhile, those with fulminant colitis requiring emergency surgery; concurrent active clostridium difficile infection of the colon; concurrent cytomegalovirus infection of the colon; evidence of colonic perforation; massive hemorrhage from the colon requiring emergent surgery in the 6 months prior to screening; ulcerative, indeterminate, microscopic, ischemic, or infectious colitis; neoplasia of the colon; presence of an ostomy; 3 or more prior small bowel resections; previous colonic resection; or a colonic stricture that is unable to pass an adult colonoscope will be excluded from the study. Additional inclusion and exclusion criteria exist.

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In addition to the phase 1 trial in CD, ExoFlo is also being evaluated in a phase 1 clinical trial for medically refractory ulcerative colitis (NCT05176366) and in the pivotal phase 3 EXTINGUISH ARDS clinical trial (NCT05354141) for patients who have been hospitalized for moderate-to-severe acute respiratory distress syndrome from any cause, including COVID-19.2,3 Direct Biologics also recently received clearance of an investigational new drug application from the FDA for a separate phase 1b/2a clinical trial (NCT05836883) in medically refractory perianal fistulizing CD in April 2023.4

“We are excited to announce the initiation of our CD clinical trial as we expand our ExoFlo clinical development program into inflammatory bowel disease,” Lightner said of the phase 1 trial in CD in a March 2023 statement.1 “CD is a debilitating lifelong condition that affects every aspect of daily life. With this new trial of ExoFlo, we are seeking to further illustrate the potential antiinflammatory, immunomodulatory, and regenerative properties of ExoFlo, each of which we believe to be crucial in the treatment of CD.”

Direct Biologics is not the only company to have evaluated an MSC-derived therapy for the treatment of CD. Celularity previously conducted several phase 1 clinical trials evaluating a placental-derived mesenchymal-like adherent stromal cell therapy approach to treating CD. Although these legacy trials did not meet the Celularity’s expectations, the company currently has a newer product, APPL-001, in the preclinical stages of development for CD.5

“...I have said repeatedly that I don't believe the MSC studies have failed, I believe the study designs have failed the MSCs,” Adrian Kilcoyne, MD, MPH, MBA, the chief medical officer of Celularity, said in a 2023 interview with CGTLive regarding Celularity’s legacy trials. “I think now with our understanding of the mode of action, we can design the end points a lot better [and] we can design the time points a lot better so what we may have are longer studies, but with the appropriate end points.”

1. Direct Biologics announces initiation of phase 1 clinical trial for medically refractory Crohn’s disease. News release. Direct Biologics, LLC. March 21, 2023. Accessed November 30, 2023.
2. Direct Biologics announces first patient dosed with ExoFlo in a phase 1 clinical trial for medically refractory ulcerative colitis.News release. Direct Biologics, LLC. March 28, 2023. Accessed November 30, 2023.
3. Direct Biologics reports compelling data as ExoFlo™ expanded access program in hospitalized COVID-19 patients with moderate-to-severe ARDS surpasses 100 subjects. News release. Direct Biologics, LLC. April 19, 2023. Accessed November 30, 2023.
4. Direct Biologics receives FDA clearance to initiate phase 1b/2a clinical trial of ExoFlo™ in patients with medically refractory perianal fistulizing Crohn’s disease. News release. Direct Biologics, LLC. April 26, 2023. Accessed November 30, 2023.
5. Allogeneic Placental-Derived Product Candidates. Celularity. Website. Accessed November 30, 2023.
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