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come instruments will be utilized in a phase III trial. With the caveat of limited sample size and exposure, no safety concerns emerged during the study other than those described; in particular, infectious events were rare, clini- cally mild, and self-limiting, irrespective of unchanged danicopan treatment. Although the short study duration through the primary endpoint limits the ability to draw
robust conclusions, the data do not appear to support the postulated increased risk of infectious complications (due to upstream inhibition of the complement cascade),27 in agreement with in vitro data showing that killing of encap- sulated and unencapsulated meningococci was nearly unaffected relative to that occurring with eculizumab.28,29
Danicopan is the first oral complement inhibitor treat-
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Figure 2. Effect of danicopan on lactate dehydrogenase and hemoglobin levels. (A) Change in lactate dehydrogenase (LDH) concentration from baseline (day 1) to day 28 was the primary efficacy endpoint. LDH reduction per patient is shown here including the reduction from a mean value of 5.7±2.17 times upper limit of normal (ULN) at baseline to 1.8±1.03 times ULN at day 28 (P<0.001) demonstrating achievement of the primary endpoint. A significant mean LDH reduction from baseline was sustained throughout the study up to day 84 (2.2±1.04 times ULN; P<0.001). (B) Per patient effects on hemoglobin with a mean group increase from 9.8 g/dL at baseline (day 1) (range, 6.9 to 12.0 g/dL) to 10.9 g/dL at day 28 (range, 8.4 to 14.1 g/dL; P<0.005), and 11.5 g/dL at day 84 (range, 8.7 to 13.7 g/dL, P<0.005). Note, patient 3 received a protocol waiver to enter the study despite the <12 g/dL hemoglobin inclusion criterion. For the sponsor and site investigator, the hemo- globin level did not represent a clinically meaningful difference relative to the threshold in the protocol and the patient had significant hemolysis, as evidenced by LDH values. **P<0.005; SD:standard deviation.
Figure 3. Effect of danicopan on blood transfusions and Functional Assessment of Chronic Illness Therapy-Fatigue score. (A) Two patients required transfusions dur- ing the trial, for a total of nine units on four occasions over 84 days. The transfusion history (84 days prior to screening through to the end of the study; sum for all patients) is provided. (B) Mean Functional Assessment of Chronic Illness Therapy–Fatigue score values (± standard deviation) at baseline (day 1) through to the end of the study (day 84) with descriptive statistics. The range of scores was 0 to 52; a score of <30 indicates severe fatigue. *P<0.05; **P<0.005. Note, data were not obtained for one patient at day 56. FACIT: Functional Assessment of Chronic Illness Therapy; SD: standard deviation.
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haematologica | 2021; 106(12)