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Table 1. Baseline characteristics and clinical results.
Patient 1* Patient 2 Patient 3§ Patient 4° Patient 5 Patient 6 Patient 7# Patient 8 Patient 9 Patient 10*
BL D28 D84 BL D28 D84 BL D28 D84 BL D28D84 BL D28 D84 BL D28 D84 BL D28 D84 BL D28 D84 BL D28 D84 BL D28 D84
Danicopan (mg po tid) 100 150 175 100 150 175 150 175 200 150 175 - 150 175 175 150 150 150 150 175 - 150 175 175 150 175 200 150 150 150
2.34 0.88 0.47 11 41 43
0.4 -† 0.1
2.40 0.94 1.05 36 49 58
0.1 -† 0.1
0.58 0.35 - 24 38 -
0.3 -† -
0.41 0.41 0.41 18 33 42
0.1 0.1 0.1
Danicopan, an oral factor D inhibitor for PNH
Hb (g/dL)
LDH (xULN) Reticulocytes (109/mL) Total bilirubin (mg/dL) GPI-deficient RBC
clone size (%) C3d+ RBC (%) FACIT-Fatigue††
7.5 9.3 8.7 11.7 14.1 12.3 12.0 11.8 13.7 11.7 12.6 - 10.4 10.2 10.9 9.2 11.2 11.4 8.7 10.2 - 9.5 10.2 11.6 10.0 11.4 11.9 6.9 8.4 11.1 3.76 2.64 2.36
84 76 69 0.53 0.70 0.41 20 31 36
0.1 -† 0.1
22 33 31 32 47 49 42 43 52 23 36 - 22 23 40 20 52 52 49 51 - 44 49 50 39 46 46 47 52 52
7.39 2.22 3.27 150 71 85
3.60 0.77 0.94 80 42 45
1.63 0.89 0.90 45 55 49
7.93 0.90 2.50 236 38 105
1.17 0.23 0.53 78 82 78
0.1 -† 0.4
0.83 1.04 - 20 - -
0.5 0.1 -
8.55 1.51 3.26 217 74 48
1.88 0.88 0.74 21 47 59
0.2 -† -⁋
6.08 2.29 2.98 171 78 118
1.32 0.54 0.71 13 35 42
0.1 -$ -⁋
6.02 0.80 1.02 249 109 130
1.64 0.35 0.41 75 37 92
0.1 0.3 0.1
BL: baseline; D: day; po: orally; tid: three times a day; Hb: hemoglobin; LDH: lactic acid dehydrogenase; ULN: upper limit of normal; GPI: glycosylphosphatidylinositol; RBC: red blood cells; FACIT: Functional Assessment of Chronic Illness Therapy. *Patient reported a history of aplastic anemia. †C3 fragment deposition was not tested for day 28; no data entry for this visit. ††Scores based on the FACIT-Fatigue Scale V4; score range 0-52 (a score <30 indicates severe fatigue). §Patient received a protocol waiver to enter the study despite the <12 g/dL Hb inclusion criterion; for the sponsor and site investigator,the Hb 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. °Patient withdrew due to personal reasons not related to safety (day 40).#Patient withdrew due to a serious adverse event (day 51). ⁋C3 fragment deposition was not tested at day 84;no data entry for this visit. $Incorrect container type.
Efficacy
Primary endpoint
Change in LDH concentration from baseline to day 28 was the primary efficacy endpoint. A significant reduction was observed in all ten patients from a mean value of 5.7±2.17 times ULN at baseline to 1.8±1.03 times ULN at day 28 (P<0.001) (Figure 2A, Table 1), demonstrating achievement of the primary endpoint. The percentages of patients showing LDH <3 times ULN, <2 times ULN, and <1 time the ULN were 90%, 60%, and 40%, respectively.
Secondary endpoints
Significant reductions in LDH from baseline were sus- tained throughout the study, with values being 2.3±1.41 times ULN at day 56 (P<0.005) and 2.2±1.04 times ULN (P<0.001) at day 84 (Figure 2A). The percentages of patients with LDH <3 times ULN, <2 times ULN, and <1 time ULN were 71%, 43%, and 43% at day 56, and 75%, 37.5%, and 25% at day 84, respectively. Danicopan is a highly permeable drug and even in patients with high body mass index, plasma concentrations do not appear to cause a clinically significant change in effect. Fluctuations in LDH indicated that low-level residual intravascular hemolysis remained in most patients, with possible tran- sient exacerbations; this was due to transient weaker AP inhibition around predose periods, as described above, in addition to an increase of susceptible GPI-deficient ery- throcytes during treatment (see below). Nevertheless, only two breakthrough hemolytic events were recorded by the investigator as adverse events (Table 2); a third patient experienced recurrent subclinical breakthrough episodes as a consequence of inadequate control of com- plement activation.
Treatment with danicopan translated into an improve- ment of anemia: mean hemoglobin increased from 9.8 g/dL at baseline (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), 10.9 g/dL at day 56 (range, 8.5 to 13.1 g/dL; P<0.005), and 11.5 g/dL at day 84 (range, 8.7 to 13.7 g/dL; P<0.005) (Figure 2B, Table 1). The mean increase from baseline was 0.9 g/dL at day 28 and 1.7 g/dL at day 84. In the 12 weeks preceding study entry, two patients received transfusions (Figure 3A). One of these patients, who had aplastic anemia (not receiving immunosuppressive therapy), had received five transfu- sions totaling ten units. During treatment, this patient received three transfusions totaling seven units. The sec-
ond patient had one transfusion (two units) during break- through hemolysis in the setting of a viral infection; in this case, danicopan treatment was not detrimental to the course of the infection, but (irrespective of its possible effect on other complement pathways) did not effectively counteract the transient acute complement activation (possibly due to pharmacokinetic/pharmacodynamic rea- sons). The remaining patients in the trial were transfusion independent through the 84 days of treatment. Accompanying the control of intravascular hemolysis and improvement of anemia, patient-reported outcomes were assessed. The mean FACIT–Fatigue score at baseline was 34 and increased by 9 and 13 points at days 28 and day 84, respectively (P<0.05) ( Figure 3B, Table 1).
Control of intravascular hemolysis by danicopan was further confirmed by changes in other laboratory parame- ters. Danicopan significantly increased the percentage of GPI-deficient erythrocytes (56±19.9% at day 84 vs. 32±24.6% at baseline; P=0.001), whereas no change was observed for GPI-deficient granulocytes (Figure 4A). Total bilirubin decreased after danicopan treatment (0.6±0.23 mg/dL at day 84 vs. 1.3±0·74 mg/dL at baseline, P<0.05) (Figure 4B). A sustained but not statistically increase in haptoglobin was observed (15.3±16.08 mg/dL at day 84 vs. 5.8±2.89 mg/dL at baseline; P=0.15) (Online Supplementary Figure S3A), as was a transient decrease in free hemoglobin (83±51 mg/dL at day 28 vs. 138±132 mg/dL at baseline; P=0.26) (Online Supplementary Figure S3B). Absolute reticulocyte count decreased quickly and was sustained with treatment (81±33.6×109/L at day 84 vs. 154±69×109/L at baseline; P<0.05) (Figure 4C). Additional laboratory results can be found in Online Supplementary Table S6.
Exploratory endpoints
To investigate the mechanistic effect of proximal com- plement inhibition by danicopan on PNH, complement biomarkers were monitored. Bb fragment, an activation product of factor B, tracks complement AP activation in vivo. Plasma Bb level was significantly elevated at base- line (2.24±0.77 mg/mL) compared with that in healthy vol- unteers (0.84±0.212 mg/mL; P<0.05). After danicopan, the Bb levels were significantly reduced: 0.84±0.84 mg/mL at day 28 (P<0.005); 0.47±0.09 mg/mL at day 56 (P<0.005); and 0.47±0.06 μg/mL at day 84 (P<0.005) (Figure 1C). In contrast to residual AP activity, Bb level remained consis-
5.09 1.84 - 170 109 -
6.68 3.95 - 137 50 -
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