Paroxysmal nocturnal hemoglobinuria perspective: Lactate Dehydrogenase (LDH) as a surrogate endpoint

Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired, life-threatening blood disorder that results in uncontrolled complement activity and intravascular hemolysis (IVH). The associated complications include anemia, fatigue, abdominal pain, hemoglobinuria, erectile dysfunction, and thrombosis, among other manifestations; this nonspecific and variable symptomatology complicates diagnosis and assessment. A number of treatments for PNH are available, with clinical trials historically using the change in hemoglobin level as a primary endpoint; however, no well-established ‘optimal’ outcome exists for use in such studies. In this article, we examine the suitability of lactate dehydrogenase (LDH) as a surrogate endpoint for PNH in patient care and clinical trial design. LDH is released into the circulation during IVH and provides a direct, early, and reliable measure of disease activity in PNH. Elevated LDH, across a broad dynamic range, has been associated with many PNH complications: it is a significant predictor of risk of thromboembolic events (TE), unlike hemoglobin, with higher risk estimates than hemoglobin also for impaired renal function and mortality. In addition, a clinically significant reduction in LDH levels is associated with reductions in TE and the degree of transfusion dependence, which can also be independent of hemoglobin concentration. LDH has been proven as a reliable, early indicator of therapeutic efficacy, demonstrating a rapid and robust response to complement inhibition, often within the first days to weeks of treatment. In our expert opinion, LDH should be considered as a surrogate endpoint for trials in PNH, potentially facilitating earlier and more efficient patient access to effective and/or patient-friendly treatment options for this life-threatening disease.