A Phase II Study to Evaluate the Safety and Efficacy of Defibrotide in Sickle Cell Disease-Related Acute Chest Syndrome (IND 127812)

Background: Acute Chest Syndrome (ACS) is the greatest contributor to the morbidity and mortality of Sickle Cell Disease (SCD) patients with a rate of 12.8 cases per 100 patient-years. The mortality rates of ACS are 4 times higher in adults than in children (Children 1.1% vs Adults 4.3%) (Vichinsky et al, Blood, 1997). The root cause of ACS in SCD is related to endothelial dysfunction (Paul et all, European Journal of Hematology 2011). While existing therapies target infection, inflammation, and alveolar hypoxia, they do not work to repair loss of integrity within the endothelial barrier that ultimately causes ACS. Defibrotide is a polydisperse mixture of predominantly single stranded oligonucleotides derived from porcine intestinal mucosa. Several pre-clinical studies indicate that Defibrotide primarily protects endothelium, particularly in small vessels, and appears to reduce endothelial cell injury (Falanga et al, Leukemia, 2003). In a randomized, phase III study, a decrease in incidence of SOS/VOD was observed in pediatric hematopoietic stem cell transplantation patients who received prophylactic Defibrotide (Corbacioglu et al, 2012). We hypothesized that Defibrotide is safe and well tolerated in SCD-associated ACS.

Primary Aims: To determine the safety and efficacy of defibrotide in the treatment of SCD-associated ACS.

Design/Methods: Patients with SCD- (Homozygous Hemoglobin S disease, Hemoglobin SC Disease or Hemoglobin Sβ^0/+ Thalassemia) associated ACS aged 2 to 40 years of age were enrolled. Defibrotide, generously supplied by Jazz Pharmaceuticals, was administered at 6.25 mg/kg IV Q6H (total daily dose 25 mg/kg/day) within 24 hours of consent and continued for 7 days or until the patient was discharged from hospital, whichever occurred first (IND 127812) (NCT 03805581). All patients were treated with current standard of care, including: antibiotics, analgesics, oxygen, intravenous fluids, and packed red blood cells (PRBC)/exchange transfusion. Complete blood counts and coagulation studies were performed at baseline, day 7 and day 30, while chest radiograph (CXR), CT chest angiogram (CTA), pulmonary function test (PFT), and transthoracic echocardiogram (ECHO) were performed at baseline and 30 days after Defibrotide was first given for disease assessment.

Results: We have enrolled 20 patients (median age 9.5 years) with a gender ratio of M/F 8/12. Patients had hemoglobin SS (n=14), hemoglobin Sβ^0/+ (n=2), or hemoglobin SC (n=4). The median doses of Defibrotide per patient was 18.5 (range 6-28) and the average hospital admission length was 6.1 days (range 3-13 days). There were no serious adverse events probably or directly related to Defibrotide, as judged by investigators. Two patients had a grade I/II epistaxis that did not disrupt Defibrotide's course. Pulmonary infiltrate on CXR and/or CTA was the most common finding at diagnosis, with 18/20 participants (90%) (Figure 1a). Thirteen patients had fever as a presenting symptom, and the average duration of the fever from diagnosis was 2.8 days (range 1-6 days) (Figure 1b). Nine patients required O₂ supplementation, with an average duration of 4.1 days (range 2-7 days). Among patients who underwent Day 30 CXR or CTA, 87.5% and 92%, respectfully, showed improvement or resolution of pulmonary consolidation, only 4 patients had a day 30 ECHO, however, all of them had a resolution of previous findings. Thirteen patients were treated with blood transfusions with a median of 1.9 units (PRBC unit was defined as 15ml/kg) transfused per patient (range, 1-5 units) and 1 patient underwent an exchange transfusion.

Conclusion: Our data suggests that Defibrotide is safe and well tolerated in SCD patients with ACS. No serious adverse events were observed. A randomized phase II/III multi-center clinical trial will need to be conducted to further investigate its efficacy.

Cooke:jazz pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cairo:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Sobi: Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Omeros: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; NEKTAR: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miltenyi: Research Funding; Merck: Research Funding; Celularity: Research Funding.