Enjaymo (Page 4 of 7)

14 CLINICAL STUDIES

14.1 CADENZA

The efficacy of ENJAYMO was assessed in a placebo-controlled 6-month trial in 42 patients (CADENZA, NCT 03275454). Following the completion of the 6-month treatment period (Part A) in which 22 patients received ENJAYMO and 20 patients received placebo, 39 patients (19 patients on ENJAYMO and 20 patients on placebo) continued to receive ENJAYMO in a long-term safety and durability of response extension phase (Part B) for an additional 12 months following last patient out from Part A. The trial included a 9 week safety follow-up after the last dose of ENJAYMO. Patients with a confirmed diagnosis of CAD based on chronic hemolysis, polyspecific direct antiglobulin test (DAT), monospecific DAT specific for C3d, cold agglutinin titer ≥64 at 4°C, an IgG DAT ≤1+ and no history of transfusion within 6 months, or more than one blood transfusion in the 12 months prior to enrollment in the trial were administered 6.5 g or 7.5 g ENJAYMO (based on body weight) intravenously over approximately 60 minutes on Day 0, Day 7, and every 14 days thereafter; or placebo. Patients with cold agglutinin disease secondary to infection, rheumatologic disease, systemic lupus erythematosus, or overt hematologic malignancy were excluded, whereas patients with a history of or concomitant low-grade lymphoproliferative disease were not excluded.

Major baseline characteristics of the study population are summarized in Table 5.

Table 5: Baseline Characteristics of Patients Included in CADENZA
Parameter Statistic CADENZA
Placebo ENJAYMO
N=20 N=22
*
Placebo N=18 and ENJAYMO N= 20 in CADENZA, for bilirubin data excluding patients with either a positive or no available test result for Gilbert’s syndrome.
ULN: Upper limit of normal, FACIT: Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue is measured on a scale of 0 (worst fatigue) to 52 (no fatigue)
Age Mean 68.2 65.3
Min, Max 51, 83 46, 88
Sex
Male n (%) 4 (20.0) 5 (22.7)
Female 16 (80.0) 17 (77.3)
Body weight Mean, Kg 64.9 66.8
Min, Max 48, 95 39, 100
Hemoglobin Mean, g/dL 9.33 9.15
Bilirubin (total) * µmol/L 35.77 41.17
(1.75 × ULN) (2 × ULN)
LDH U/L 380.8 421.5
History of transfusion Mean number of transfusions (range)
Within last 6 months 0 0
Within last 12 months 0 0.14 (0, 1)
FACIT -Fatigue scale Mean 32.99 31.67

Efficacy was based on the proportion of patients who met the following criteria: an increase from baseline in Hgb level ≥1.5 g/dL at the treatment assessment time point (mean value from Weeks 23, 25, and 26), no blood transfusion from Week 5 through Week 26, and no treatment for CAD beyond what was permitted per protocol from Week 5 through Week 26. Efficacy was further assessed based on the effect of ENJAYMO on Hgb, laboratory measures of hemolysis including mean change from baseline in total bilirubin and LDH. Supportive efficacy data collected included transfusion usage after five weeks of treatment. In addition, mean change from baseline in symptoms and impacts of fatigue were assessed using a patient-reported outcome instrument, the FACIT-Fatigue (score range from 0 to 52 with higher scores indicating less fatigue).

The data from this study demonstrated a statistically significant treatment effect of ENJAYMO over placebo in terms of the rate of patients who met the efficacy criteria (responder) as well as improving symptoms and impacts of fatigue (FACIT-Fatigue). The responder rate difference between ENJAYMO and placebo was 58.78% (95% CI: 34.6% to 82.96%) with a p-value of 0.0004. At the treatment assessment timepoint (TAT), 16 of 22 patients on ENJAYMO (72.7%; 95% CI: 49.8% to 89.3%) and 3 of 20 patients on placebo (15.0%; 95% CI: 3.2% to 37.9%) met primary criteria. Efficacy of ENJAYMO in the inhibition of hemolysis in patients with CAD was demonstrated across multiple end points as described in the table below (see Table 6).

Table 6: Efficacy Results in Patients with CAD in the CADENZA Part A Study
Parameter Statistic Placebo N=20 ENJAYMO N=22 Treatment Effect
*
A responder was defined as a patient with an increase from baseline in Hgb level ≥ 1.5 g/dL at the treatment assessment time point (mean value from Weeks 23, 25, and 26), no blood transfusion from Week 5 through Week 26, and no treatment for CAD beyond what was permitted per protocol from Week 5 through Week 26.
The Mantel-Haenszel stratum-weighted estimator of the rate difference with 95% CI was calculated using the Sato variance estimator. The stratification factors are baseline hemoglobin (< median vs ≥ median) and geographic region (Asia/Other, North America, and Europe)
LS: Least Square, FACIT-Fatigue: Functional Assessment of Chronic Illness Therapy-Fatigue Scale NC= Not calculated
§
Prohibited therapies included rituximab alone or in combination with cytotoxic agents
Responder * n (%) 3 (15) 16 (72.7) 58.78 (34.6, 82.96)
p-value: <0.001
Hemoglobin Mean change from baseline (LS Mean), g/dL 0.09 2.66 2.56
95% CI of LS Mean (1.75, 3.38)
p-value: <0.001
Patients with mean change from baseline of: greater than or equal to 1.5 g/dL n (%) 3 (15) 16 (72.7) NC
Patients not receiving blood transfusion from Week 5 through Week 26 (transfusion avoidance) n (%) 16 (80) 18 (81.8) NC
Patients not receiving protocol-prohibited CAD medications from Week 5 through Week 26 § n (%) 20 (100) 19 (86.4) NC
FACIT -Fatigue Mean change from baseline (LS Mean) 1.91 10.83 8.93
95% CI of LS Mean (4, 13.85)
p-value: <0.001

During Part A, an increase in mean hemoglobin level of 2.02 g/dL was observed in patients on ENJAYMO at Week 3; in the placebo group the mean hemoglobin level decreased by 0.31g/dL. At treatment assessment timepoint, a mean decrease in bilirubin of 1.29 mg/dL compared to baseline was reported in patients on ENJAYMO (n=17) versus 0.11 mg/dL on placebo (n=18). In the ENJAYMO group, bilirubin levels normalized in 88.2% (n=15) of patients compared to 22.2% (n=4) of patients in the placebo arm. At treatment assessment timepoint, a mean decrease in LDH of 150.83 U/L compared to baseline was reported in patients on ENJAYMO (n=19) versus an increase of 7.6 U/L on placebo (n=20). In the ENJAYMO group, LDH levels were < 1.5 × ULN in 94.7% (n=18) of patients compared to 70% (n=14) in the placebo arm.

In Part B, mean hemoglobin levels were maintained at >10.5 g/dL. Sustained normalization of mean bilirubin levels was also observed indicating a sustained decrease in hemolysis. Mean hemoglobin level of 11.58 g/dL (range: 6.90–15.30) and 1.01 mg/dL (range: 0.29–5.54) for bilirubin was observed at the last on-treatment visit.

After the last dose of ENJAYMO in the study, signs and symptoms of recurrent hemolysis were observed, nine weeks after the last dose in Part B; mean hemoglobin decreased by 2.41 g/dL (SE: 0.373) and mean bilirubin increased by 1.27 mg/dL (SE: 0.182) from the last available values during treatment.

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