Anita Hill, MD, PhD, Global Medical Head for Hematology & Nephrology and Transplant at Alexion, AstraZeneca Rare Disease, discusses recent data on ravulizumab in rare hematologic conditions.
Thrombotic Microangiopathies Following Hematopoietic Stem Cell Transplantation (HSCT-TMA)
Abstract #1052: Outcomes in pediatric patients with HSCT-TMA treated with ravulizumab.
TMAs are a group of rare disorders that cause blood clots and damage to the walls of the smallest blood vessels in the circulatory system. The blood clots can cause injury to organs that may lead to organ failure and death. HSCT-TMA is a rare and severe type of TMA that occurs following HSCT. A key driver of this disease is terminal complement activation.
The objective of this study was to evaluate protocol-defined complete and partial TMA responses, hematologic response, survival, and nonrelapse mortality (NRM) after treatment with ravulizumab in children with HSCT-TMA. Ravulizumab is a monoclonal antibody against C5.
A phase 3, open-label, single-arm trial (NCT04557735) of ravulizumab was conducted in pediatric patients who: 1) received HSCT within 12 months; 2) had HSCT-TMA persisting 72 hours or more despite initial management; and 3) weighed 5 kg or greater. Participants received weight-based loading doses on days 1, 5, and 10, and maintenance doses every 4 weeks (weight less than 20 kg) or 8 weeks (weight 20 kg or greater) from day 15 through week 26. The trial enrolled a total of 41 patients, with 28 completing the 26 week treatment period.
By week 26, complete TMA response was observed in 17.1% participants and hematologic response occurred in 24.4% participants. As individual components of hematologic response, 58.5% and 36.6% participants met the platelet (including transfusion independence) and lactate dehydrogenase response criteria, respectively. Hemoglobin response of 10 g/dL or greater, including absence of red blood cell transfusions, was observed in 41.5% participants. The presence or absence of schistocytes varied throughout the study with no clear trends. Protocol-defined complete or partial TMA response occurred in 70.7% meeting 1 or more criterion. The Kaplan-Meier estimate of overall survival was 92.6% at 100 days and 87.2% at 26 weeks. All deaths during the treatment period, a total of 5, were due to NRM; causes of death were multiorgan failure, hypoxic respiratory failure, heart failure, and septic shock.
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Abstract #4266: Organ dysfunction in pediatric patients with HSCT-TMA treated with ravulizumab
The objective of this study was to describe protocol-defined organ dysfunction, including the renal, cardiopulmonary, central nervous, and gastrointestinal systems, at baseline and 6 months in children with HSCT-TMA treated with ravulizumab during the phase 3 trial (NCT04557735).
Cardiopulmonary involvement at TMA diagnosis was reported in 70.7% of participants at baseline. At week 26, 36.7% had cardiopulmonary involvement. Gastrointestinal pain was observed in 19.5% of participants at baseline and 6.7% at week 26. Gastrointestinal bleeding was observed in 4.9% at baseline and 3.3% at week 26. Central nervous system dysfunction was reported in 7.3% of participants at baseline and 10.0% at week 26. Participants presented with significantly elevated median urine protein-creatinine ratio at 2.50 mg/mg at baseline that decreased to 0.43 mg/mg by week 26. Median change from baseline was −2.54 mg/mg. Median estimated glomerular filtration rate was 114 mL/min/1.73 m2 at baseline and 102 mL/min/1.73 m2 at week 26. Median change in baseline was 3.4 mL/min/1.73 m2.
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Paroxysmal Nocturnal Hemoglobinuria (PNH)
Abstract #949: Danicopan add-on therapy demonstrates positive efficacy and safety outcomes in advanced age adults with paroxysmal nocturnal hemoglobinuria and clinically significant extravascular hemolysis: A sub-analysis of the phase 3 ALPHA trial
PNH is a rare, chronic, progressive and potentially life-threatening blood condition characterized by red blood cell destruction within blood vessels and white blood cell and platelet activation, which can result in thrombosis. It is caused by an acquired mutation in the PIGA gene that may happen any time after birth, resulting in the production of abnormal blood cells that are missing protective proteins. These missing proteins enable the complement system to attack and destroy or activate these abnormal blood cells. Signs and symptoms may include blood clots, abdominal pain, difficulty swallowing, erectile dysfunction, shortness of breath, excessive fatigue, anemia and dark-colored urine.
In the phase 3 ALPHA clinical trial (NCT04469465), add-on therapy with danicopan, a first-in-class oral factor D inhibitor, was shown to significantly improve clinical outcomes in adult patients on ravulizumab or eculizumab and with clinically significant extravascular hemolysis (csEVH). The objective of this study was to characterize the efficacy and safety of danicopan add-on therapy in patients with advanced age with PNH and csEVH.
A total of 86 patients were enrolled in ALPHA, with 57 randomized to add-on danicopan and 29 to add-on placebo. In the danicopan arm, both age groups showed an increase in mean hemoglobin concentration from baseline to week 1, which was maintained in patients ages 65 years and older and improved in those aged less than 65 years through to week 12.
During this period, both age groups also demonstrated a meaningful reduction in mean absolute reticulocyte count (ARC) and increases in FACIT-F score, which was more pronounced in patients aged less than 65 years. In comparison, there were no notable improvements in mean hemoglobin concentration, ARC or FACIT-F from baseline to week 12 in the placebo arm. In the danicopan arm, the proportion of patients who were transfusion independent at week 12 was similar between patients aged 65 years and greater and less than 65 years (75.0% vs 80.5%, respectively) and was higher compared with those in the placebo arm.
The proportion of patients in the danicopan arm who experienced an adverse event during 12 weeks of add-on therapy was similar between patient age groups. Additionally, in both groups, the proportion of patients experiencing an adverse event was lower in the placebo arm, particularly in those aged 65 years and greater.
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Pregnancy and Ravulizumab
Abstract #4458: Safety of ravulizumab use in pregnancy: Insights from a global pharmacovigilance analysis
The objective of this analysis aimed to provide insights into pregnancy-related safety following ravulizumab exposure using data from global post-marketing surveillance. An analysis of all pregnancy cases reported globally in the post-marketing setting of ravulizumab, with 1 or more documented dose of exposure, was conducted. A total of 256 pregnancy cases with 1 dose or more of ravulizumab exposure were identified.
Hematologic conditions represented a substantial proportion of underlying maternal diagnoses. Of the non-hematologic conditions, underlying maternal diagnosis included generalized myasthenia gravis and neuromyelitis optica spectrum disorder. Among 79 cases with data on pregnancy outcomes, the distribution of ravulizumab exposure included full-pregnancy exposure in 26.6%, ravulizumab to eculizumab switch during pregnancy in 26.6% and incomplete exposure details reported in 43.1%. Pregnancy outcomes included live births, spontaneous abortions, fetal deaths, and elective terminations.
Moreover, in a subset of 38 pregnancies more detailed information was available on ravulizumab exposure. Maternal co-morbidities reported, predominantly in PNH, were aplastic anemia, Budd-Chiari syndrome, hypertension including gestational, and gestational diabetes. In this subset, 29 were live births, of which, 16 had ravulizumab exposure throughout all trimesters, 3 had exposure beyond 12 weeks but discontinued prior to delivery, and 8 had exposure limited to the first trimester.
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To learn more about PNH and other rare hematologic conditions, visit https://checkrare.com/diseases/hematologic-disorders/
Tags: hematology, autoimmune, metabolic, drug development, treatment