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Key Studies in Nonmalignant Hematology: Independent Conference Coverage of ASH 2020

Hanny Al-Samkari, MD
Mark A. Schroeder, MD
Sujit Sheth, MD
Released: February 11, 2021

Hereditary Blood Disorders

Phase III HOPE-B: Etranacogene Dezaparvovec in Severe or Moderately Severe Hemophilia B

Sujit Sheth, MD:
At ASH 2020, Pipe and colleagues[13] presented preliminary efficacy and safety data from the phase III HOPE‑B study, an international, open‑label, single‑arm trial of etranacogene dezaparvovec gene therapy in patients with moderate-severe or severe hemophilia B, including with anticapsid-neutralizing antibodies (N = 54).

Hemophilia B is typically treated with coagulation factor IX (FIX) replacement therapy in regular IV infusions. By contrast, etranacogene dezaparvovec is a gene therapy that aims to establish sustained FIX activity with a single treatment, eliminating the need for frequent prophylaxis and improving quality of life.[14-16] It consists of an adeno-associated virus-5 vector with a naturally occurring hyperactive Padua FIX gene variant (AAV5-Padua hFIX).

Participants were adult males 18 years of age or older with a FIX activity level no more than 2% of normal; the severe category is typically defined as less than 1%. They had to have been receiving continuous FIX prophylaxis for at least 2 months. HOPE-B had 2 primary endpoints: FIX activity at 26 and 52 weeks (coprimary endpoints); the annualized bleeding rate at 52 weeks was compared with the lead-in phase. Secondary endpoints included safety and rates of total, spontaneous, traumatic, and treated and untreated bleeds. Additional endpoints included FIX consumption and response rate correlated with AAV5 neutralizing antibodies—this is a key aspect of the study design because the gene of interest is carried in an AAV5 vector. Patients received 1 dose of etranacogene dezaparvovec 2 x 1013 gc/kg, with follow-up extending to 60 months.

Phase III HOPE-B: Baseline Characteristics

Sujit Sheth, MD:
Patients enrolled on HOPE-B had a median age of 41.5 years; 81.5% of patients had severe hemophilia B, with FIX activity less than 1.0%, and 18.5% of patients had moderate or severe disease, which was defined in this study as FIX activity ranging between ≥ 1% and ≤ 2%. The percentage of patients testing positive for HIV or who had previous hepatitis B or hepatitis C infection was 5.6%, 5.6%, and 50%, respectively. Of importance, approximately 43% of patients had detectable neutralizing AAV5 antibodies at baseline, and the max titer recorded was over 3 thousand. During the lead-in phase, 16 patients reported bleeds (29.6%) and there was a total of 123 cumulative bleeds.

Phase III HOPE-B: FIX Activity at 26 Weeks

Sujit Sheth, MD:
After the single infusion, FIX levels increased until about Week 6. By Month 6, mean FIX activity levels were 37.2% or a +36.01% increase from baseline (P < .0001). Achieving and maintaining stable FIX activity in the 30% to 50% range would be protective of most bleeds, and was observed across the entire population of 54 patients at the 6-month time point.

Phase III HOPE-B: Activity Beyond 26 Weeks

Sujit Sheth, MD:
The investigators also presented data beyond 26 weeks, up to 12 months in some patients: n = 35 at 7 months, 14 at 10 months, 4 at 11 months, and 3 at 12 months. Of importance, the study showed that FIX levels have remained fairly stable in patients with data beyond 6 months, with no apparent decline in factor IX activity beyond 26 weeks; 1 patient had a FIX activity level of approximately 40% at 18 months of follow-up.

Phase III HOPE-B: Preexisting NAb Titers and FIX Activity

Sujit Sheth, MD:
Another important finding of the HOPE-B study was that there was no correlation between response and preexisting neutralizing AAV5 antibodies titer, which is important because it was previously believed that patients with neutralizing antibodies would not be good candidates for this type of gene therapy. There was a single exception to this observation of a patient with a very high antibody titer of 3212.3 who did not respond to treatment. This observation suggests that there may be a threshold of antibody level above which you might not necessarily be a good candidate, but all others who had levels that were lower, up to a titer of 678, did actually have a response.

Phase III HOPE-B: Bleeds and FIX Replacement in the First 26 Weeks

Sujit Sheth, MD:
At the 26-week time point, there was a significant reduction in total bleeds (83% decrease) and treated bleeds (91% decrease) vs baseline. There was also a significant decrease in factor usage, decreasing from a mean of 290,769 units/year/patient at baseline to 12,537 units/year/patient at 26 weeks in all 54 patients; 52 (98%) patients were also able to discontinue their previous prophylaxis indefinitely.

Phase III HOPE-B: Safety

Sujit Sheth, MD:
The safety profile of autologous etranacogene dezaparvovec gene therapy was quite good. Rates of treatment-related AEs were low and 76% were mild in severity. Influenza like illness (13.0%), headache (13.0%), and liver enzyme elevation (alanine aminotransferase, 13.0%; aspartate aminotransferase, 9.3%) were the most common AEs after treatment with the AAV5 virus–associated vector. Nine of 54 patients had some elevation of liver enzymes that required intervention with steroids, but all had discontinued steroids before the 6 month analysis.

Seven patients experienced infusion related reactions, but the infusion was able to be completed in 6 of them; 1 patient received 10% of the dose and discontinued treatment thereafter. Of importance, there was no correlation between AAV5 capsid–neutralizing antibodies and safety, and no inhibitors to FIX were reported.

Phase III HOPE-B: Conclusions

Sujit Sheth, MD:
HOPE-B is the largest phase III study of gene therapy for hemophilia B to date. At ASH 2020, data were reported for the primary analysis, showing that in patients with moderately severe to severe hemophilia B, etranacogene dezaparvovec significantly increased mean FIX activity to near-normal levels by 6 months. Immunosuppression was not required for all and 98% of patients responded and were able to discontinue FIX prophylaxis. There were no major treatment-related AEs. Thus, the study is very encouraging because it recapitulated what was shown previously in the supporting phase IIb study in the same patient population.[15,16]

The HOPE-B study is ongoing, and data will be collected for up to 60 months. It will be interesting to see what longer‑term data show and whether durability of FIX activity is extended.

CLIMB THAL-111/SCD-121: Phase I/II Studies of CTX001 for Transfusion-Dependent β-Thalassemia and SCD

Sujit Sheth, MD:
At ASH 2020, early results from 2 phase I/II studies of CTX001 were presented (N = 45 in each study).[17] This is an autologous gene-edited hematopoietic stem cell therapy for the treatment of severe hemoglobinopathies in patients with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD). CTX001 comprises hematopoietic stem and progenitor cells modified at BCL11A using CRISPR/Cas9 technology.[18] The modifications made to patients’ cells are designed to downregulate BCL11A gene expression, which allows continuing gamma globin expression and therefore fetal hemoglobin production.

CLIMB THAL‑111 enrolled patients 12-35 years of age with TDT including β00 genotypes who were eligible for an autologous stem cell transplant (ASCT); 7 treated patients are included in this report. CLIMB SCD‑121 enrolled patients 12-35 years of age with severe SCD and at least 2 severe vaso-occlusive crises in the past 2 years who were eligible for ASCT; 3 treated patients are included in this report.

The primary endpoint in CLIMB THAL 111 was a sustained reduction in transfusions of 50% for at least 6 months, beginning 3 months after the infusion. The primary endpoint for CLIMB SCD-121 was a fetal hemoglobin level of 20% or more sustained for longer than 3 months, beginning 6 months after the infusion.

Similar to other studies of gene therapy,[19,20] the manufacturing of CTX001 in both these trials involved collecting autologous stem cells (after plerixafor or granulocyte colony-stimulating factor mobilization), isolating the CD34-positive cells and editing them with CRISPR-Cas9, then expanding and reinfusing the engineered cells after myeloablative conditioning with busulfan.

CLIMB THAL-111: AE Overview for Patients With ≥ 3 Months of Follow-up

Sujit Sheth, MD:
In CLIMB THAL-111, most AEs occurred within the first 60 days of the infusion, and all were consistent with complications expected and related to the myeloablation and the ASCT. In the 7 patients with at least 3 months of follow-up, only 1 reported a serious AE related or possibly related to the treatment itself.

CLIMB THAL-111: Hemoglobin Outcomes for Patients With ≥ 3 Months of Follow-up

Sujit Sheth, MD:
Results in patients with TDT and at least 3 months of follow-up are very promising. Following infusion of CTX001, total hemoglobin levels reached near normal range for most patients with a significant proportion of that hemoglobin being fetal hemoglobin (fetal hemoglobin/total hemoglobin levels: 11.1 g/dL/12.0 g/dL, 10.6 g/dL/11.6 g/dL, or 11.1 g/dL/12.2 g/dL). Also, by Month 9, nearly 100% of peripheral blood were F-cells, which means that there is fetal hemoglobin in virtually every cell generated in the bone marrow (ie, pan‑cellular distribution of fetal hemoglobin.)

CLIMB THAL-111: Hemoglobin Outcomes by Genotype for Patients With ≥ 3 Months of Follow-up

Sujit Sheth, MD:
All 7 patients in the β-thalassemia population were non‑β00. Data for individual patients at various times demonstrated that fetal hemoglobin levels increased from 0-0.3 g/dL at baseline to approximately ≥ 10 g/dL by Month 6 in 4 of 5. Total hemoglobin levels at the 6-month evaluation timepoint were between 10 and 14 g/dL in all 5 patients.

CLIMB THAL-111: Transfusion Independence for Patients With ≥ 3 Months of Follow-up

Sujit Sheth, MD:
All evaluable patients with TDT achieved transfusion independence with varying hemoglobin levels (range: 9.7-14.1 g/dL). Even though the data are not yet fully mature, the study has far exceeded its primary endpoint of reducing transfusion burden by 50% for longer than 6 months, beginning 3 months after the CTX001 infusion.

The duration of response was quite striking, with on-study time without the need for RBC infusions ranging from 1.8-20.5 months, with the remaining 5 patients between approximately 4 and 10 months.

CLIMB THAL-111: Durable BCL11A Allelic Editing

Sujit Sheth, MD:
In patients with TDT or SCD and at least 6 months of follow-up (n = 5 and 2, respectively), durable BCL11A allelic editing was seen in bone marrow CD34-positive cells. At 6-month visits, allelic editing was noted in 41.8% to 88.1% of cells in the 7 patients. By Month 12, allelic BCL11A editing was still evident in 2 patients (76.1% and 80.4% of cells). One patient with TDT had 78.1% of cells with BCL11A editing at 6 months and 76.1% at 12 months, and 1 patient with SCD had 81.4% of cells with BCL11A editing at 6 months and 80.4% at 12-month, showing remarkable stability between the 6-month and the 12-month values.

CLIMB SCD-121: AE Overview for Patients With ≥ 3 Months of Follow-up

Sujit Sheth, MD:
Safety signals in the SCD population were in line with that of the β-thalassemia population and consistent with expected complications from myeloablation and ASCT.

Most AEs occurred within the first 60 days after the infusion, and there were no AEs that were only related to CTX001. This is consistent with other gene therapy studies where safety concerns have mostly related to the transplant procedure itself.[19,20]

CLIMB SCD-121: Hemoglobin Outcomes for Patients With ≥ 3 Months of Follow-up

Sujit Sheth, MD:
Hemoglobin responses in patients with SCD were quite robust, with all 3 patients achieving total hemoglobin levels ≥ 10 g/dL by 3 months. All 3 patients with SCD went from being anemic to having near-normal hemoglobin levels (patient 1: from 7.2 g/dL to 12 g/dL; patient 2: from 6 g/dL to 11.5 g/dL; patient 3: from 9.2 to 13.2 g/dL), with follow-up ranging from 3-15 months.

The percentage of sickle hemoglobin decreased by approximately 50%, with the remaining 50% comprised mostly of fetal hemoglobin, resulting in a favorable fetal hemoglobin/sickle hemoglobin ratio and ameliorating the sickling process. All 3 patients, albeit at different time points, achieved peripheral blood F-cell percentages > 90%; patient 1 reached 98.1% F-cells by Month 15. As in TDT, F-cell percentages > 90% strongly suggest pan-cellular distribution of fetal hemoglobin. This is of tremendous benefit, especially in SCD where the sickling process can be disrupted by fetal hemoglobin.[21]

CLIMB SCD-121: VOC-Free Duration for Patients With ≥ 3 Months of Follow-up

Sujit Sheth, MD:
A reduction in vaso-occlusive crises (VOC), after engraftment and after elevation of fetal hemoglobin levels, was observed for all 3 patients with SCD. On-study times without VOC were 3.8 months, 7.8 months, and 16.6 months. There was no evidence of ongoing hemolysis, which suggests stabilization of the red cells by the fetal hemoglobin levels.

CLIMB THAL-111/SCD-121 Studies: Conclusions

Sujit Sheth, MD:
Results from the proof-of-concept CLIMB THAL-111 and CLIMB SCD-121 studies demonstrated that allelic editing of BCL11A for reactivation of fetal hemoglobin in patients with TDT and SCD is feasible. Among the first 10 individuals with at least 3 months of follow-up, CTX001 infusion achieved cessation of RBC transfusions for patients with TDT and eliminated VOC events for patients with severe SCD.

Current data show stable engraftment of modified CD34-positive cells for at least 6-12 months. Data also show pan-cellular distribution and high allelic editing of stem cells as well as a high fetal hemoglobin level, which was maintained throughout follow-up in all patients. Observed safety parameters were in line with expectations for patients undergoing busulfan-mediated myeloablative conditioning and ASCT. A prospective, long-term follow-up study of patients from both CLIMB THAL-111 and CLIMB SCD-121 is underway.[22]

Phase I Trial of Mitapivat (AG-348) in SCD

Sujit Sheth, MD:
At ASH 2020, Xu and colleagues[23] presented results from an ongoing, multiple ascending-dose, phase I study of the pyruvate kinase R inhibitor mitapivat in patients 18 years of age or older with stable SCD, including hemoglobin ≥ 7 g/dL at baseline. Mitapivat acts as an anti-sickling agent in RBCs by reducing 2,3-DPG and increasing ATP levels.[24,25] In previous studies, mitapivat was shown to improve anemia in patients with pyruvate kinase R deficiency and β-thalassemia. Patients 1-7 received doses every 2 weeks ranging from 5-50 mg, and patients 8-12 received 5-100 mg. At Week 9, the mitapivat dose is tapered over 12-15 days.

The primary endpoints are safety, tolerability, and markers of hemolysis (changes in hemoglobin and hemolytic markers). Secondary endpoints included biochemical parameters in the RBCs, including the pharmacokinetics as well the 2,3‑DPG levels, and ATP production.

Phase I Trial of Mitapivat: Safety

Sujit Sheth, MD:
The safety profile was not significantly different from baseline. In other words, the AEs seen in this study are typical and expected for SCD and unlikely to be related to the study drug.

No patient experienced a VOC during the dose-escalation phase, although 2 patients had a VOC during the 28 day safety follow-up and 1 while tapering.

Phase I Trial of Mitapivat: Efficacy

Sujit Sheth, MD:
In the 11 patients with data to date, the mean maximal increase in hemoglobin was 1.3 g/dL (standard deviation: 0.8 g/dL), with ≥ 1 g/dL increase in 6 patients, and a mean maximal increase in hemoglobin level of 1.9 g/dL (standard deviation: 0.7 g/dL).

The pharmacokinetic analyses showed linear measurements up to 50 mg, with enzyme induction, and therefore some reduction in exposure, after the 50-mg dose.

There was a dose-dependent decrease in 2,3‑DPG levels and an increase in ATP levels, which are key markers of interest within RBCs. Of importance, a consistent decrease of hemolytic markers was noted (including bilirubin, lactate dehydrogenase, and absolute reticulocyte count) during the dose-escalation phase, but this returned to near baseline by the end of the study.

Phase I Trial of Mitapivat: Conclusions

Sujit Sheth, MD:
These are early safety and efficacy data for mitapivat in SCD that, together, suggest evidence of a biochemical effect of mitapivat on the RBCs that contain sickle hemoglobin.

In this proof-of-concept phase I trial, mitapivat twice daily was well tolerated in patients with SCD, and the safety profile was in line with previous studies of mitapivat in patients with pyruvate kinase deficiency and β-thalassemia. Efficacy included decreased 2,3-DPG levels and increased ATP levels, reduced hemoglobin and hemolytic markers, and an increase in hemoglobin ≥ 1 g/dL in more than one half of patients with accompanying lower levels of hemolysis markers.

A planned extension study will further evaluate long-term safety, tolerability, pharmacokinetic/pharmacodynamic, and mitapivat dosing in patients with SCD from this trial.[26]

BELIEVE: HRQoL Outcomes for Transfusion-Dependent β-Thalassemia Treated With Luspatercept

Sujit Sheth, MD:
BELIEVE was a randomized, double-blind, placebo-controlled phase III study of luspatercept plus best supportive care vs best supportive care alone in patients with TDT (N = 336). At ASH 2020, the health‑related quality-of-life (HRQoL) outcomes from BELIEVE were presented by Cappellini and colleagues.[27] Patients in this study required regular RBC transfusions and had not experienced more than 35 days without a transfusion. Treatment comprised luspatercept 1 mg/kg subcutaneously every 3 weeks vs placebo every 3 weeks, both with best supportive care. After Week 48, the study was unblinded and patients in the placebo arm were allowed to cross over to luspatercept with treatment continuing for up to 5 years.

The primary QoL endpoint was changes from baseline between groups up to Week 48 in HRQoL outcomes. Scales used included transfusion-dependent quality of life (TranQoL) and the Physical Health and SF-36 Health Survey (physical component summary, physical functioning, and general health). Exploratory HRQoL endpoints included improvement in scores for patients responding to luspatercept (defined using either reduction in the transfusion burden or transfusion independence over time).

Phase III BELIEVE HRQoL: SF-36 Domains and TranQoL Scores

Sujit Sheth, MD:
Overall, baseline SF‑36 scores were not different in most patients compared with the general population. The SF-36 scores were impaired vs the general population in terms of physical role, general health, and emotional role. This is understandable because of the cumbersome nature of the disease, and the stress and anxiety related to the disease itself. Patients must undergo frequent transfusions, other treatments, monitoring, and follow-up.

The SF‑36 scores were mostly unchanged from baseline to Week 48 for general health, physical functioning, and the physical component summary. TranQoL scores also remained mostly unchanged up to Week 48 for total and physical health measures.

Phase III BELIEVE HRQoL: Correlation of Number of Units Transfused and SF-36 and TranQoL Scores

Sujit Sheth, MD:
There was no correlation between the number of units of RBCs that were transfused with either the SF‑36 or TranQoL scores at Weeks 24 and 48.

Phase III BELIEVE HRQoL: Clinically Meaningful Improvements at Week 48

Sujit Sheth, MD:
There were clinically meaningful improvements in SF-36 scores at Week 48 for patients who both achieved a response and had at least a 50% reduction of transfusion burden at any 12-week transfusion interval with luspatercept vs placebo. Compared with placebo, this group experienced significant improvement in the physical functioning (13.2% vs 30.0%, respectively; P = .007) and physical component summary (16.5% vs 31.1%, respectively; P = .024) domains of the SF-36 health survey questionnaire. By contrast, changes in the SF-36 general health scores and TranQoL total and physical health components were not statistically significant between luspatercept and placebo.

Phase III BELIEVE HRQoL: Transfusion Independence at Week 24 With Luspatercept

Sujit Sheth, MD:
Looking specifically at the 9 luspatercept-treated patients who became transfusion independent, on the SF-36 scale, physical functioning scores (55.6% vs 16.5%; P = .015) and physical component summary scores (55.6% vs 19.8%; P = .028) were both significantly improved vs placebo. These findings are expected, particularly for patients who become transfusion independent. By contrast, TranQoL scores for total and physical health were not meaningfully different between luspatercept and placebo.

Phase III BELIEVE HRQoL: Conclusions

Sujit Sheth, MD:
In the HRQoL assessments from the BELIEVE study in TDT, the combination of luspatercept and BSC meaningfully reduced transfusion burden while sustaining TranQoL and SF-36 scores to Week 48 vs placebo. Patients with TDT responding to luspatercept were more likely to achieve clinically meaningful improvements in HRQoL vs placebo. A key limitation of this study is that a main benefit of luspatercept, that is, reduction of RBC transfusion visits, is not captured in the TranQoL or SF-36 measures. Another limitation is that allowing transfusions at any time to manage anemia may confound results because HRQoL was assessed at prespecified time points.

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