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Danicopan, an oral factor D inhibitor for PNH
ment demonstrating efficacy and safety in PNH patients as monotherapy in a phase II study. The clinical effects observed were achieved irrespective of low-level, residual intravascular hemolysis, which remained detectable in some patients. This residual intravascular hemolysis is likely the consequence of the increase of GPI-deficient erythrocytes susceptible to complement-mediated hemol- ysis and the pharmacokinetic/pharmacodynamic charac- teristics of danicopan. Danicopan plasma level and AP activity also correlated with in vivo biomarkers (LDH and Bb), and Bb seems a reliable indicator of complement acti- vation in vivo during danicopan treatment. Based on the results of the phase I single-dose and multiple ascending- dose trials in healthy human volunteers, 200 mg tid was shown to be both safe and efficacious.26 However, in this cohort of patients, full blockade of AP activity was not consistently achieved in all patients, irrespective of indi- vidual dose adjustment and the broad dose ranges used during the study. These observations suggest that residual intravascular hemolysis is due to low residual AP activity observed in some patients, which may be better inhibited by a more potent second-generation factor D inhibitor analog that will be assessed for safety and efficacy in a phase II trial (Clinicaltrials.gov, NCT04170023). In a con- current phase II trial, patients (n=12) on a stable regimen
of eculizumab with hemoglobin <10 g/dL and who were transfusion dependent (≥1 red blood cell transfusion with- in 12 weeks of screening) received oral danicopan 100–150 mg tid, with possible response-based dose escalation to 200 mg tid at predefined time points. The addition of dan- icopan led to clinically and statistically significant reduc- tions in frequency of red blood cell transfusions and in the number of transfused units in patients compared to those in patients with a history of eculizumab treatment alone.30
Clinical development of proximal complement inhibitors has been motivated by the description of C3- mediated extravascular hemolysis as a mechanism driving significant anemia and limiting hematologic benefit in some PNH patients on eculizumab and other C5 inhibitors.17,31 Indeed, it is conceivable that, in combina- tion with C5 inhibitors, proximal inhibitors can address C3-mediated extravascular hemolysis by preventing the generation of C3 convertase, eventually leading to better hematologic response in PNH patients.17,31 Moreover, it has been hypothesized that proximal inhibitors, by pre- venting generation of downstream C5 convertases, could be effective even in the absence of terminal inhibitors (i.e., eculizumab or other C5 inhibitors). Danicopan is the first compound demonstrating that proximal complement inhibitors can be used safely and effectively as monother-
AB
C
Figure 4. Additional clinical efficacy evaluation of danicopan. (A) The mean (± standard deviation) clone size percentages displayed for GPI-deficient ery- throcytes and granulocytes at baseline (day 1) through to the end of the study (day 84) and mean (± standard deviation) percentage of erythrocytes with C3 fragment deposition with descriptive statistics for GPI-deficient erythrocytes. Descriptive statistics for GPI-deficient granulocytes and erythrocytes with C3 fragment deposition are listed in Online Supplementary Table S6. Erythrocytes with C3 fragment deposition are defined as erythrocytes that stain positive for anti-C3d antibody. (B) Total bilirubin at baseline (day 1) through to the end of the study (day 84) with descriptive statistics. Data for one patient were not obtained at day 56. (C) Absolute reticulocyte count at baseline (day 1) through to the end of the study (day 84) with descriptive sta- tistics. Data for one patient were not obtained at day 56. *P<0.05; **P<0.005. SD: standard deviation; GPI: glycosylphosphatidylinositol.
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