CME
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: March 01, 2022
Expiration: February 28, 2023
Sujit Sheth, MD:
SCD is an inherited disease characterized by a mutation in the beta globin gene resulting in the production of hemoglobin S, or sickle hemoglobin.25 When deoxygenated, hemoglobin S polymerizes and deforms red blood cells (RBCs). The resulting cell sickling and increased cell adhesion promotes vaso-occlusion and vascular disease, which can affect all the organs and tissues of the body. Patients with SCD experience hemolysis and anemia, vaso-occlusion, end-organ damage, pain, fatigue, and a markedly reduced life expectancy.
Etavopivat is a small molecule allosteric activator of erythrocyte pyruvate kinase (PKR).26 Etavopivat activates both the wild type and mutant PKR, thereby increasing PKR activity in RBCs and resulting in decreased 2,3-diphosphoglycerate (2,3 DPG) levels and increased levels of ATP in RBCs. In a phase I study, a single dose of etavopivat in patients with SCD showed increased RBC oxygen affinity, decreased sickling, improved deformability, and improved membrane function.27
Sujit Sheth, MD:
At ASH 2021, Kalfa and colleagues28 presented results from a randomized, placebo-controlled phase I dose-escalation study of etavopivat in patients with SCD aged 12-65 years with ≤6 vaso-occlusive crises in the prior 12 months and no packed RBC transfusions within 30 days of dosing. Concomitant use of hydroxyurea was permitted. The etavopivat dose was escalated from 300 mg/day to 600 mg/day for 2 weeks, followed by transition to an open-label extension phase where patients received 400 mg/day for 12 weeks. The study objectives were to assess the effect of etavopivat on markers of RBC health, including ATP, 2,3 DPG, oxygen affinity, RBC enzyme activity or pyruvate kinase activity, sickle cell deformability, membrane damage, and RBC indices and the effect on markers of sickle cell pathophysiology, including inflammation, coagulation, and hypoxia.
Sujit Sheth, MD:
As shown in the figure on the left, RBC cell ATP increased while on treatment and decreased again when patients were tapered off therapy. The figure on the right shows a decrease in 2,3 DPG while on treatment that means an increase in oxygen affinity, which is again reversed back to baseline after a 4-week washout period.
Sujit Sheth, MD:
The figure on the left shows what happens to the 2,3 DPG levels before (blue squares) and after (red circles) administration of etavopivat. As shown in this figure, 2,3 DPG levels are lower after etavopivat administration, and as a result, the figure on the right shows that the oxygen saturation curve shifts to the left, which means increased oxygen affinity as a result of that decrease in 2,3 DPG. In other words, the sickle cell oxygen affinity normalized to hemoglobin A affinity following etavopivat administration and reversed back after treatment was stopped.
Sujit Sheth, MD:
Study investigators also showed the results of an oxygen scan of RBC deformability. The utility of this scan is controversial as it is very challenging to reproduce. Nevertheless, the investigators performed this deformability assay and showed that patients on etavopivat experienced an improvement in RBC deformability. Of note, sickle cell deformability improved over 12 weeks of treatment with etavopivat.
Sujit Sheth, MD:
Regarding markers of RBC health, hydration improvements were noted by 2 weeks of treatment with etavopivat and remained sustained over the 12-week period. Investigators also observed an improvement in hydration as evidenced by decreased cellular hemoglobin concentration. Furthermore, investigators noted significantly increased PKR activity from baseline (P <.001), improved RBC redox potential (P <.001), and decreased phosphatidylserine expression on the outer membrane (P <.01)—a marker of increased adhesiveness—at 2 weeks of therapy. Finally, markers of inflammation, hypercoagulability, and hypoxia were significantly decreased (P <.05 to P <.001) while receiving etavopivat.
Sujit Sheth, MD:
In summary, up to 12 weeks of treatment with etavopivat resulted in increased ATP and decreased 2,3 DPG in patients with SCD; normalization of the hemoglobin S oxygen affinity to hemoglobin A; a significant reduction in sickling; improved sickle red blood cell deformability and hydration; and an improvement in markers of red blood cell health, as well as a reduction in markers of inflammation, hypercoagulability, and hypoxia. According to the investigators, the effects of etavopivat may reduce vaso-occlusion and end organ damage in patients with SCD, which supports moving etavopivat to the next phase of clinical development with larger numbers of patients and clinically meaningful endpoints.
Sujit Sheth, MD:
At ASH 2021, we also saw the results from a phase I multiple ascending-dose study of mitapivat (AG-348), another oral activator of PKR.29 Mitapivat has been shown to have similar effects to etavopivat in terms of reducing 2,3 DPG and increasing ATP levels.30,31 The analysis by Xu and colleagues reports final safety, tolerability, and SCD-related. Patients received increasing doses of mitapivat every 2 weeks from 5 mg up to 100 mg for some patients. Patients 1-7 escalated from 5 mg to 50 mg and patients 8-12 escalated from 5 mg to 100 mg. This was followed by a taper at Week 9 over 12-15 days, and follow-up was done at 4 weeks thereafter. Patients were allowed to be on other concomitant drugs, such as hydroxyurea and L-glutamine. The primary endpoint was safety, tolerability, and changes in hemoglobin and hemolytic markers; secondary endpoints were pharmacokinetics, 2,3 DPG and ATP levels, oxygen affinity, and sickling tendency, which was measured by hemoglobin S polymerization.
Sujit Sheth, MD:
Most baseline patient characteristics were unremarkable except that 12 out of 17 patients (70.6%) were receiving hydroxyurea and one was receiving L-glutamine at the same time. Patients had elevated reticulocytes (188.2 K/µL), anemia (with a mean hemoglobin level of 9.2 g/dL), elevated LDH (375.2 U/L) and bilirubin (2.0 mg/dL)—all of which are markers of hemolysis in patients with SCD.
Sujit Sheth, MD:
Of the 17 patients enrolled, 1 was withdrawn per investigator decision, and 6 completed the study per protocol up to the 50-mg dose escalation.
The remaining 10 patients escalated to the 100-mg dose and 9 completed the study per protocol at this dose (1 withdrew per patient decision).
Sujit Sheth, MD:
Treatment-related AEs were mostly grade 1/2 and grade ≥3 AEs were reported in 17.6% of patients. Grade ≥3 AEs included hypertension (5.9%), vaso-occlusive crisis (VOC; 11.8%), anemia (5.9%), and fatigue (5.9%). No patient experienced VOC during dose escalation; 2 patients developed VOC during drug tapering phase, which was thought to be possibly drug-related. Consequently, the trial protocol was amended to extend the length of taper. Finally, 2 patients developed VOC during a 28-day safety follow-up period, which were associated with established VOC triggers and were reported to be unrelated to study drug.
Sujit Sheth, MD:
Serious AEs of VOC were reported in 4 patients (23.5%), shoulder pain in 1 patient (5.9%), and pulmonary embolism in 1 patient (5.9%). None required drug discontinuation. Grade 3 hypertension occurred in 1 patient who already had grade 2 hypertension at baseline, and anemia and fatigue occurred in 1 patient following drug taper.
Sujit Sheth, MD:
Regarding changes in hemolytic markers, the investigators showed that as mitapivat dose was escalated, hemoglobin changes went from nonsignificant to significant. Furthermore, the hemoglobin level was similar at the 50-mg twice-daily dose or 100-mg twice-daily dose—approximately 1.0 g/dL over baseline—but decreased once the drug was tapered and at the end of the study. There was a consistent decrease in markers of hemolysis (LDH, bilirubin, absolute reticulocyte count, and aspartate aminotransferase) during the dose escalation, all of which returned to near baseline by the end of the study.
Sujit Sheth, MD:
Mitapivat demonstrated linear pharmacokinetics with doses up to 50 mg. There was a reduction in exposure observed after multiple doses of 100 mg compared with the first 100-mg dose, meaning that patients did not continue to absorb as much or have as much exposure to the drug after the first 100-mg dose. Therefore, 50 mg is probably the dose that will be selected going forward, especially because the hemoglobin levels achieved were similar with these 2 doses.
There were also dose-dependent decreases in 2,3 DPG levels and p50 observed during active treatment with mitapivat, similar to what we saw with etavopivat and followed by a return to normal once the drug was withdrawn. Moreover, there were dose-dependent increases in ATP levels and t50 observed during active treatment, again followed by a return to normal for both once the drug was withdrawn. Of note, the p50 is defined as the partial pressure of oxygen at which oxygen saturation is 50%, and the t50 is defined as the time in minutes at which 50% of RBCs are sickled in response to gradual deoxygenation, which is a different way of looking at that sickling index compared with what was shown with etavopivat.
Sujit Sheth, MD:
In the final safety analysis of mitapivat, investigators concluded the drug is safe and well tolerated at multiple ascending doses in patients with SCD. Moreover, in this phase I trial, hemoglobin increased by 1.0 g/dL in 56% of patients and patients had lowered markers of hemolysis. Finally, 2,3 DPG decreased and ATP levels increased, with corresponding increases in oxygen affinity and decreases in the rate of sickling. These data provide proof of concept support that mitapivat improves anemia and decreases hemolysis in patients with SCD, which would justify advancing mitapivat to the next phase in clinical development.
Sujit Sheth, MD:
There is currently a need for more effective therapy to reduce the frequency of VOCs and associated complications in pediatric patients with SCD. P-selectin expressed by endothelial cells and platelets during inflammation and trauma contribute to painful VOCs.32 Crizanlizumab is a first-in-class humanized monoclonal antibody that binds to P-selectin.33 The SUSTAIN trial evaluated crizanlizumab 5 mg/kg in patients with SCD 16 years of age or older and demonstrated significant reductions in the median annualized rate of VOCs compared with placebo.1
The phase II SOLACE-kids study of crizanlizumab was designed to confirm and establish the optimal dosing and assess safety in pediatric patients with SCD.34 At ASH 2021, Heeney and colleagues reported data from Group 1 of SOLACE-kids in patients ages 12 to younger than 18. Crizanlizumab was administered intravenously on Week 1, Day 1, Week 3, Day 1, and then every 4 weeks for up to 2 years. The primary endpoints included pharmacokinetics, pharmacodynamics assessments, and safety. Secondary endpoints included annualized rate of VOCs leading to a healthcare visit, VOCs treated at home, hospitalizations, emergency department visits, and other safety measures.
Sujit Sheth, MD:
This table shows the baseline characteristics for Group 1 of the study. The median age was 14.9 (range: 12.0-17.9); 58% of patients were female; 64% were Black or African American; and the most predominant genotype was HbSS in 88% of patients, with 4% each for HbSC, HbS𝛽0, and HbS𝛽+ phenotype. Patients were treated with crizanlizumab 5 mg/kg and 88% (44/50) of patients completed 26 or more weeks of treatment.
Sujit Sheth, MD:
In terms of safety, there were no new safety signals compared with those observed in the SUSTAIN trial.1 Liver function parameters did change, but they were transient, possibly related to fluctuating hemolysis in these patients. No treatment-related AEs related to hemostasis or infection were noted.
The most common AEs were headache (28%), vomiting (24%), and back pain (18%); and the most common treatment-related AEs were infusion-related reactions (8%), back pain (6%), vomiting (4%), dizziness (4%), and nausea (4%). Eight (16%) patients required dose interruption, but most were able to restart treatment.
Sujit Sheth, MD:
A total of 6 potentially severe infusion-related reactions, defined as events more likely to be caused by the infusion and to potentially have a more severe clinical course, occurred but none was greater than grade 3; 4 of the 6 were thought to be treatment-related. Signs or symptoms indicative of a possible infusion-related reaction occurred in 15 patients; 1 was grade ≥3 and 11 were considered to be treatment-related. Potential infusion-related reactions presenting as pain events were observed in eight patients; 1 was grade ≥3 and 3 were considered to be related to the treatment. No patients developed antidrug antibodies against crizanlizumab.
Sujit Sheth, MD:
This table on the right compares the AEs of special interest from SOLACE-kids with those in SUSTAIN. Data were comparable between the two studies, which is reassuring because nothing stands out as being particularly different or concerning in patients ages 12 to younger than 18 vs patients 16 years of age or older.
Sujit Sheth, MD:
In terms of the efficacy, a reduction in the median annualized rate of VOCs was observed compared with baseline when receiving crizanlizumab (3.0 at baseline vs 1.61 when receiving crizanlizumab). Moreover, there also was a reduction in the median annualized rate of hospitalizations or emergency department visits with crizanlizumab (4.0 at baseline vs 1.54 when receiving crizanlizumab). Finally, 18 patients (36%) did not experience a single VOC leading to a healthcare visit during crizanlizumab treatment with a median duration of treatment of 36.6 weeks.
Sujit Sheth, MD:
Based on these data, the investigators concluded that crizanlizumab is well tolerated in patients ages 12 to younger than 18, and the overall profile was consistent with what they saw in adults.1 In terms of efficacy, the 5 mg/kg was associated with a clinically relevant reduction in the median annualized rate of VOCs leading to healthcare visits compared with baseline. This trial is now ongoing with dose confirmation in Group 2, which includes patients aged 6 to younger than 12 years.
Taken together, I am hopeful that these data will ultimately help lead to approval of crizanlizumab for younger pediatric patients because there is clearly an unmet need for therapies that will reduce pain crises in this population of patients with SCD.
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