Complement in Sickle Cell Disease: Are We Ready for Prime Time?

Figures & data

Table 1 Summary of Novel Approved and Under Development Therapies in SCD

Mechanism	Clinical Trials’ Results	Status
1) Selectin inhibitors
Crizalinzumab (humanized anti-P selectin mAB)	Reduction in number of pain crisis	FDA approved
Rivapansel (pan-selectin inhibitor)	Reduction in opioid use during VOC	Pending
Sevuparin (anti P-selectin heparin derivative)	Possible preventive use	Pending
2) Adenosine and invariant NK T cells
Regadenoson (A2A receptor agonist)	Decreased activation of invariant NK T Cells	Pending
3) Leukotrienes
Zileuton (5 lipo-oxygenase inhibitor)	Well tolerated both in children and adults	Pending
Mometasone (ínhaled corticosteroid)	Reduction in pain scores	Pending
3) Antioxidants
l-Glutamine (NADH production)	Reduction in VOC events	FDA approved
N-acetylcysteine (enhances glutathione, weakens oxidative stress)	Diary data suggest no impact on pain scores - lab measures of VWF activity under evaluation	Pending
4) Enhanced nitric oxide bioavailability
l-Arginine (NO substrate)	Reduction in opioid use and pain scores	Pending
IMR-687 (PDE9 inhibitor)	Reduction in VOC and opioid use	FDA has granted rare pediatric disease designation
5) Other agents
Voxelotor	Inhibition of red cell sickling – reduction in hemolysis	FDA Approved

Figure 1 Complement activation and inhibition. The complement cascade has been traditionally considered to be activated by the classical, alternative and lectin pathway. The alternative pathway serves as an amplification loop for the lectin and classical pathway accounting for almost 80% of complement activation products. Spontaneous hydrolysis of C3 resulting from different triggers allows propagation of C3 convertase (C3bBb) and as a result the alternative pathway is constantly “on”. C3 convertase sustains the amplification loop together with factors B and D. Terminal complement pathway begins with propagation of C5 convertase which in turn cleaves C5 into C5a, a potent inflammatory mediator, and C5b; C5b together with C6-9 form C5b-9 (membrane attack complex/MAC), a cytolytic complex. Eculizumab, ravulizumab, ABP959, SKY59/RO7112650, tesidolumab, REGN3918, mubodina, coversin, RA101495, cemdisiran and zimura inhibit C5; AMY-101 and APL-2 inhibit C3 and C3 convertase activity; mini-FH/AMY-201 inhibits alternative pathway C3 convertase; LPN023 and IONIS-FB-LRx inhibit factor B; danicopan and lampalizumab inhibit factor D; mirococept inhibits C3 and C5 convertases; avacopan inhibits C5a receptor and IFX-1 C5a.