Complement C3 inhibition in severe COVID-19 using compstatin AMY-101

Abstract

Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 ( n = 16) or placebo ( n = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101–treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug’s inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.

Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors

“…This increased capacity to bind and protect the C3 substrate rather than targeting C3b opsonins may confer an additional benefit in indications that are not exclusively driven by the alternative pathway or massive C3b deposition. Finally, the 20-fold size difference between pegcetacoplan and Cp40 may also affect tissue penetration of the unbound drugs.In recent clinical trials, pegcetacoplan treatment resulted in a marked increase in plasma C3, whereas no comparable target elevation could be observed during dosing with the monovalent AMY-101 12,38 . It will be critical to elucidate the clinical relevance of the distinct target binding profiles to guide the application of different compstatin-derived drugs in the future.…”

C3 Targeted Complement Therapy for Chronic Periodontitis – A Scoping Review

“…The AMY-101 binds C3 and blocks its cleavage into C3a and C3b by C3 convertase. [ 9 15 ] Subsequently, it inhibits the amplification of the complement cascade regardless of the triggering pathway, i.e., classical, lectin or alternative. As complement activation products C3a and C5a mediate crosstalk signalling with adaptive and immune cells, C3 is a perfect target for curative modulation of complement and inflammatory pathways involved in CP[ 11 ] [ Figure 2 ].…”

“…In medicine, diabetic kidney disease and severe COVID-19 were managed with this therapy. [ 12 15 , 17 ] A potential concern regarding this therapy is plausible host antimicrobial defense impairment with long-term complement inhibition. [ 9 ] The limitations of this review are that the results were preliminary and mainly derived from the studies on NHPs.…”

A B1a–natural IgG–neutrophil axis is impaired in viral- and steroid-associated aspergillosis

“…3D). Complement is critical for host defense and antibody effector functions but can also exacerbate inflammation in infections such as COVID-19 (28)(29)(30)(31). We evaluated the role of complement, finding that exogenous transfer of complement did not explain the improvements in mice receiving serum, because heat inactivation of serum did not reduce the benefits (fig.…”