healthcare professional
PNH is a rare, chronic, life-threatening disease affecting the complement cascade – a critical part of the normal innate immune response.4 Uncontrolled terminal complement activation impairs the normal functioning of blood cells and leads to life-threatening consequences such as intravascular haemolysis (IVH), thromboembolic event, renal impairment and pulmonary hypertension.3,5
In IVH, red blood cells (RBCs) are destroyed within the bloodstream, releasing haemoglobin into plasma and causing life-threatening consequences such as thrombosis and organ damage.6,7 Elevated lactate dehydrogenase (LDH) level (≥1.5 x ULN) is a key biomarker for IVH.8
In IVH, red blood cells (RBCs) are destroyed within the bloodstream, releasing haemoglobin into plasma and causing life-threatening consequences such as thrombosis and organ damage.6,7 Elevated lactate dehydrogenase (LDH) level (≥1.5 x ULN) is a key biomarker for IVH.8
Inhibition of C5-mediated terminal complement controls IVH of PNH RBCs.9,10 Surviving PNH RBCs are susceptible to deposition of C3b fragments that may lead to the premature destruction of RBCs outside the bloodstream – often in the liver and spleen – a process called EVH.7,11
- Inhibition of C5-mediated terminal complement controls IVH of PNH RBCs.7,9-11
- The PNH RBCs remaining in circulation are susceptible to C3 fragment deposition that may lead to EVH.7,12,13
- In PNH, EVH does not indicate inadequate terminal complement inhibition7,11
In some patients EVH can lead to anaemia, as RBCs are destroyed faster than they are formed. However, for most patients with PNH receiving C5 inhibition therapy, anaemia (if present) is asymptomatic.9,10,13
Clinically significant EVH is associated with ongoing anaemia and fatigue, with consequences for patient quality of life and transfusion dependency.7,9
A subset of patients treated with a C5 inhibitor may experience cs-EVH.9,15 However, residual anaemia can be caused by several factors beyond EVH, including bone marrow dysfunction, low nutritional folate or iron overload, relative erythropoietin deficiency.9,14,16 In PNH, to confirm whether residual anaemia is due to EVH, other causes should be eliminated.17,18
A subset of patients treated with a C5 inhibitor may experience cs-EVH.9,15 However, residual anaemia can be caused by several factors beyond EVH, including bone marrow dysfunction, low nutritional folate or iron overload, relative erythropoietin deficiency.9,14,16 In PNH, to confirm whether residual anaemia is due to EVH, other causes should be eliminated.17,18
ULTOMIRIS® is the critical backbone and standard of care for PNH treatment.21 By targeting uncontrolled terminal complement activity, it delivers immediate, complete and sustained C5 inhibition‡.16,18,22-24 ULTOMIRIS® also has a well established safety profile, backed by the largest body of evidence in complement inhibitor naïve patients with PNH to date.23,25
VOYDEYA® is an approved and selective inhibitor of Factor D of the alternative pathway, deposition of C3 fragments on PNH RBCs is prevented and consequent EVH can be decreased.1
VOYDEYA® is an approved and selective inhibitor of Factor D of the alternative pathway, deposition of C3 fragments on PNH RBCs is prevented and consequent EVH can be decreased.1
*While clinically significant EVH is not defined by specific laboratory thresholds, the inclusion criteria in the Phase 3 ALPHA trial defined low haemoglobin as ≤9.5 g/dL and increased absolute reticulocyte count as ≥120×109/L.1,2
†Other causes of anaemia in patients receiving a C5 inhibitor include bone marrow dysfunction, low nutritional folate or iron levels, relative erythropoietin deficiency, breakthrough IVH, hypersplenism, iron overload and/or the presence of alloantibodies.11,18
‡Following ULTOMIRIS® treatment in both adult and paediatric complement inhibitor-naïve patients and eculizumab-experienced patients with PNH in Phase 3 studies, immediate, sustained and complete inhibition of serum free C5 (concentration of <0.5 μg/mL) was observed by the end of the first infusion and sustained throughout the entire 26-week treatment period in all patients.19,21-23
†Other causes of anaemia in patients receiving a C5 inhibitor include bone marrow dysfunction, low nutritional folate or iron levels, relative erythropoietin deficiency, breakthrough IVH, hypersplenism, iron overload and/or the presence of alloantibodies.11,18
‡Following ULTOMIRIS® treatment in both adult and paediatric complement inhibitor-naïve patients and eculizumab-experienced patients with PNH in Phase 3 studies, immediate, sustained and complete inhibition of serum free C5 (concentration of <0.5 μg/mL) was observed by the end of the first infusion and sustained throughout the entire 26-week treatment period in all patients.19,21-23
Even in the event of incomplete complement inhibition (due to infection, surgery, missed dose), dual inhibition may work synergistically to maintain disease control*.1,7,15,26
*Currently, the explanation offered for greater severity of breakthrough haemolysis with escape from C3 blockade vs escape from C5 blockade is theoretical.26
*VOYDEYA® may also be taken with SOLIRIS® (eculizumab).1
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Dosing and Administration of Voydeya®
Adverse Event Reporting
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C3b, complement component 3b; C5, complement component 5; cs, clinically significant; EVH, extravascular haemolysis; IVH, intravascular haemolysis; LDH, lactate dehydrogenase; LSM, least squares mean; PNH, paroxysmal nocturnal haemoglobinuria; RBC, red blood cell; SMPC, summary of product characteristics; ULN, upper limit of normal.