SUSTAIN

The efficacy of ADAKVEO was evaluated in patients with sickle cell disease in SUSTAIN [NCT01895361], a 52-week, randomized, multicenter, placebo-controlled, double-blind study. A total of 198 patients with sickle cell disease, any genotype (HbSS, HbSC, HbS/beta0-thalassemia, HbS/beta+-thalassemia, and others), and a history of 2-10 VOCs in the previous 12 months were eligible for inclusion. Patients were randomized 1:1:1 to ADAKVEO 5 mg/kg (N = 67), ADAKVEO 2.5 mg/kg (N = 66), or placebo (N = 65) administered over a period of 30 minutes by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter for a treatment duration of 52 weeks. Randomization was stratified by patients already receiving hydroxyurea (Y/N) and by the number of VOCs in the previous 12 months (2 to 4, 5 to 10).

Patients received ADAKVEO (with or without hydroxyurea) and were allowed to receive occasional transfusions and pain medications [i.e., acetaminophen, NSAIDs, and opioids] on an as needed basis.

Patients recruited in the study had complications associated with sickle cell disease and other comorbidities, including a history of acute chest syndrome (18%); pulmonary hypertension (8%); priapism (7%); psychiatric manifestations (25%), including depression and anxiety; hypertension (17%); cholelithiasis (17%). Demographic and other baseline characteristics were similar among the treatment groups (see Table 3).

Efficacy was evaluated in the SUSTAIN study by the annual rate of VOCs leading to a healthcare visit. A VOC leading to a healthcare visit was defined as an acute episode of pain with no cause other than a vasoocclusive event that required a medical facility visit and treatment with oral or parenteral opioids, or parenteral NSAIDs. Acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism (requiring a visit to a medical facility) were also considered VOCs.

Patients with sickle cell disease who received ADAKVEO 5 mg/kg had a lower median annual rate of VOC compared to patients who received placebo (1.63 vs. 2.98) which was statistically significant (p = 0.010). Reductions in the frequency of VOCs were observed among patients regardless of sickle cell disease genotype and/or hydroxyurea use.

Thirty-six percent (36%) of patients treated with ADAKVEO 5 mg/kg did not experience a VOC compared to 17% of placebo-treated patients. The median time to first VOC from randomization was 4.1 months in the ADAKVEO 5 mg/kg arm compared to 1.4 months in the placebo.

The main efficacy results of the pivotal study, SUSTAIN, are summarized in Table 4.

STAND

The efficacy of two doses of ADAKVEO, with or without HU/HC, was evaluated, but not established, in the STAND trial [NCT03814746], a randomized, placebo-controlled, double-blind, multicenter clinical study in adolescent and adult sickle cell disease patients with a history of VOCs. The efficacy results of STAND study are summarized in Table 6 below.

In this study, VOC was defined as a pain crisis (acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID. Acute chest syndrome (ACS), priapism and hepatic or splenic sequestration were considered VOCs in this study.

A total of 252 sickle cell disease patients were randomized to the study, 85 in placebo arm, 84 in ADAKVEO 5 mg/kg arm and 83 in ADAKVEO 7.5 mg/kg arm. The 7.5 mg/kg ADAKVEO dose is not approved and is not recommended for use. Demographic and other baseline characteristics were similar among the treatment groups (see Table 5).

The percentages for subgroups of race and genotype do not add up to 100% due to rounding to 1 decimal place. The results of the efficacy analysis did not confirm the statistical superiority of ADAKVEO over placebo in reducing VOCs leading to a healthcare visit over the first-year post randomization.