Prevention of Acute Chest Syndrome in Sickle Cell Disease
Introduction
A-001 is an intravenously administered inhibitor of sPLA2, which is in a Phase 2 clinical study for the prevention of acute chest syndrome associated with sickle cell disease. Acute chest syndrome is a form of inflammation induced lung failure and is the most common cause of death in patients with sickle cell disease. sPLA2 levels increase substantially in the 24 to 48 hours before the onset of acute chest syndrome. According to the Sickle Cell Information Center, sickle cell disease is a genetic disorder afflicting more than 70,000 people in the United States alone. Given the small patient population and lack of approved drugs for the prevention of acute chest syndrome associated with sickle cell disease, we have received orphan drug designation and fast track status from the FDA for A-001.
sPLA2 in Sickle Cell Disease
Sickle cell disease is a severe‚ life-shortening hemoglobin disorder. Its hallmark is the deformed‚ sickle–shaped red blood cell that is prone to cause organ damage by occluding small blood vessels [1]. In many patients‚ the course of the disease includes episodes of fever‚ respiratory symptoms‚ and a new lung infiltrate on a chest x–ray‚ a combination termed acute chest syndrome. Acute chest syndrome is the second most common cause of hospitalization in patients with sickle cell disease‚ and the most common cause of death. Patients suffer varying degrees of compromised lung function‚ and may require mechanical ventilation. A variety of triggers‚ including viral infections‚ and painful vascular occlusions in long bones (vaso–occlusive crises‚ or VOC)‚ can precede the illness. There are an estimated 10‚000 episodes of acute chest syndrome per year in the U.S. alone‚ and large sickle cell disease populations in the Middle East‚ Europe and Africa.
Disease Management
Treatment for the acute chest syndrome is mainly supportive (supplemental oxygen‚ etc.)‚ although the sickest patients typically receive transfusions‚ aimed in part at shifting the balance between sickle cells (misshapen and prone to vascular occlusion) and normal red blood cells. Because of antibody formation‚ safe transfusion becomes increasingly difficult to achieve in individual patients. Hydroxyurea has shown efficacy in sickle cell disease‚ but its use is limited by toxicity and variable patient compliance. Based on the severity of the syndrome‚ and the limitations of available therapies‚ a well tolerated preventive therapy has great potential value to patients with sickle cell disease.
sPLA2 and A-001 in Acute Chest Syndrome
A substantial evidence base implicates as a contributor to the acute chest syndrome‚ as proposed by Styles‚ et al. at Children’s Hospital Oakland. As shown in the figure below (left panel)‚ serum sPLA2 levels are higher in acute chest syndrome than in patients with VOC‚ patients at steady state (i.e.‚ stable sickle cell disease)‚ or patients with pneumonia. Also, as shown in the figure on the right panel, the height of the serum sPLA2 elevation also reflects the severity of the lung compromise.
To investigate the significance of sPLA2 in acute chest syndrome‚ Styles‚ et al. tracked serum sPLA2 levels in patients presenting with VOC‚ and found that they increased in all patients in advance of hospital admission for the onset of acute chest syndrome. When this group further studied sPLA2 as a marker of impending acute chest syndrome‚ they found that the combination of an elevated serum sPLA2 level (above 100 ng/mL) and fever had a diagnostic sensitivity of 100% and sensitivity of 87%. A second research group also found an elevation in serum sPLA2 to be a useful warning sign for acute chest syndrome.
A further link between sPLA2 and acute chest syndrome was provided by the finding that transfusion both lowers serum sPLA2 and prevents acute chest syndrome (Bostrom MA, et al, 2007). Regarding the latter‚ in a separate study 5 of 8 control patients with sPLA2 elevation and VOC developed acute chest syndrome‚ compared to 0 of 7 patients who received transfusion.
The presence of warning signal (elevated sPLA2 level) suggests the possibility of preventing acute chest syndrome in patients who are at–risk. This is an unusual circumstance‚ in which there is an opportunity to intervene early in the course of a serious inflammatory disorder‚ in the prodromal phase. Inhibition of sPLA2 to prevent acute chest syndrome may prove useful both in the acute setting and as maintenance therapy for patients with sickle cell disease.
Current Phase 2 Study
A pre-specified interim review of our Phase 2 clinical study results by a DSMB indicate A-001, at a certain dose, reduced sPLA2 activity by more than 80% from baseline within 48 hours. Furthermore, the incidence of acute chest syndrome appeared to be related to the level of sPLA2 activity.
For information about the Phase 2 IMPACTS trial‚ please visit the IMPACTS Trial Site.
