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Conquering SCD by Confronting Treatment Barriers, Investigating PROs


A pair of abstracts presented during this year’s 64th American Society of Hematology Annual Meeting and Exposition explored barriers to treatment for sickle cell disease (SCD).

A pair of abstracts presented during this year’s 64th American Society of Hematology Annual Meeting and Exposition explored barriers to treatment for sickle cell disease (SCD), the group of inherited blood disorders characterized by abnormal hemoglobin that cause transporting red blood cells to become hard, sticky, and C-shaped.1 Sickle cell disease can lead to painful episodes or worse. Investigators explored treatment barriers that patients and their caregivers confront2 as well as patient-reported outcomes (PROs) following administration of voxelotor, approved just last year by the FDA,3 in the ongoing ActIVe trial (NCT04400487).4,5

Barriers to SCD Treatment2

“In the absence of widespread curative therapies, disease modifying therapies (DMTs) are important treatment options to manage disease complications and improve outcomes,” a team from the University of Pittsburgh wrote. However, they added, DMTs remain underutilized.

They used a behavioral theory–informed theoretical framework to assess barriers to SCD treatment across 14 domains. Their cross-sectional, web-based survey collected data on sociodemographics, DMT use, attitudes/beliefs toward DMTs, and health system­­–related factors. Scores were determined using a scale of 1 (strongly disagree) to 5 (strongly agree). There were 100 patient/caregiver responses, with 54% of respondents noting they had a primary care provider (PCP) and a hematologist.

Knowledge, reinforcement, beliefs about consequences, and environmental were the 4 domains with notable findings. Eighty-five percent overall expressed worry about adverse effects.

Hydroxyurea (51%) was the most common DMT for the 63% of respondents reporting DMT use, voxelotor use was reported in an additional 13%, 64.2% reported needing more information on DMTs (vs 79.4% who said they understood them well), 30.4% had neutral beliefs (vs 63.0% who believe DMTs would lead to better outcomes), 50% of nonusers believe not enough information on DMTs is available, and 42% of current DMT users had a negative/neutral outlook on their health from using DMTs, indicating they do not “explicitly agree that their current health depends on the use of DMTs,” the investigators wrote.

Among the 91% reporting they had insurance coverage, 26% had commercial coverage and 25% had Medicaid. However, 41.1% reported limited access to health care stemming from treatment costs and 27.8% reported limited access because of insurance requirements.

“Overall, our study population may represent a subset of relatively high functioning individuals, given their enrollment in an insurance plan, access to a PCP and a hematologist, regular follow-up with a physician, and current use of a DMT,” the study researchers concluded. “Yet, our study population experiences significant barriers to DMT.”

To move forward, the authors noted that future studies need to encompass a more diverse patient population—in socioeconomic status, insurance status, and DMT use—and education initiatives need to focus more on DMT use in SCD, especially with newer promising pharmacological approaches in the pipeline.

Patient-Reported Outcomes5

Following its acquisition by Pfizer in October 2022,6 Global Blood Therapeutics (GBT) continues to make progress toward optimizing treatment for SCD. The $5.4 billion acquisition will enhance GBT’s ability to deliver life-changing treatments for historically underserved patient communities,7 while for Pfizer, GBT’s expertise in SCD, as well as its portfolio and drug development pipeline, will serve to reinforce the pharma giant’s commitment to finding effective treatments for rare hematological disorders.

The safety and efficacy of GBT’s voxelotor, a first-in-class hemoglobin polymerization inhibitor approved for use in patients 4 years and older who have SCD,7 had been demonstrated with the phase 3 HOPE8 (NCT03036813) and phase 2a HOPE-KIDS 19 (NCT02850406) trials. In the PRO analysis presented during ASH 2022, findings from the phase 4 ActIVe study were reported.4

Ten US sites administered 1500-mg daily voxelotor for up to 24 weeks, with the patient population (n = 25; 92.0% Black or African American; 64.0% female) being aged 12 to 55 years. Hemoglobin was measured at 3 follow-ups—2, 12, and 24 weeks after administration—and PROs were evaluated with the Patient Global Impression of Change (PGI-C) scale, the National Institutes of Health Patient-Reported Outcome Measurement Information System-43 (PROMIS-43) for adults (> 17 years), PROMIS-37 for adolescents (≤ 17 years), and a 10-point numeric rating scale (NRS) for pain intensity.

“A minimum response deemed meaningful was interpreted at the group level as a ≥ 5-point change from [baseline] in PROMIS domains,” the authors wrote, “and a ≥ 2-point change on the NRS.”

Even with 2 patients lost to follow-up, 78% saw their hemoglobin increase a mean (SD) 0.53 (0.839) g/dL by week 24.

By week 24, following clinician evaluation, most patients (84.6%) had an improved health status: 7.7% were “very much improved”, 46.2%, “much improved”, and 30.8%, minimally improved. At the same time point, patients self-reported improved health status (92.9%), which broke down to “very much improved” in 21.4%, “much improved” in 42.9%, and minimal improvement in 28.6%. Just 1 patient had worsened health status.

Fourteen patients provided PROMIS data at 24 weeks. Among the adults (n = 9), CFB was meaningful for fatigue (–8.3 [5.24]) and pain interference (–6.9 [5.43]). For the remaining domains of physical function (1.4 [2.14]), anxiety (–4.6 [8.48]), depression (–1.7 [6.79]), sleep disturbance (–4.3 [4.37]), ability to participate (4.5 [7.73]), and pain intensity (–1.0 [1.00]), improvements were considered modest. The pediatric patient population saw no changes that indicated meaningful improvement.

Few treatment-emergent adverse events (TEAEs) were seen, with 18 patients reporting at least 1 non–SCD-related TEAE and 3 reporting at least 1 grade 3 non-SCD-related TEAE. Diarrhea was the most common non–SCD-related TEAE reported (32.0%), and no grade 4 or higher TEAEs were seen.

“The safety profile reported in ActIVe is consistent with previous studies of voxelotor treatment,” the authors determined. “Overall, results suggest that voxelotor-treated patients may experience improvements in QOL [quality of life], including in their physical and emotional well-being.”

So, What’s Next?10

In June, GBT kicked off the next step in its investigation of GBT021 (GBT601) a next-generation hemoglobin polymerization inhibitor, among pediatric and adult patients. The phase 2 investigation (NCT05632354), part of a phase 2/3 international trial—with proposed sites in Africa, Europe, the Middle East, South America, and the United States—will focus on the investigational agent’s safety, efficacy, and tolerability.

The patient population could include up to 60 participants aged 18 to 65 years, with eligibility restricted to those with hemoglobin levels ranging from 5.5 to 10.5 g/dL and a maximum of 10 vaso-occlusive crises over the past 12 months. Randomization will be 1:1:1 for a GBT601 daily maintenance dose of 100, 150, or up to 200 mg, and the primary outcome is total patients with hemoglobin change from baseline through week 12.

Pediatric and adult outcomes will then be assessed in a phase 3 investigation once the optimal GBT601 dose is determined from the phase 2 analysis, and this portion will focus on 48-week efficacy and safety vs placebo. A third study arm will then evaluate single and multiple doses of GBT601 for pharmacokinetics and safety among pediatric patients.


1. What is sickle cell disease? CDC. Accessed December 16, 2022. https://www.cdc.gov/ncbddd/sicklecell/facts.html

2. Kazarov C, Novelli EM, Kane-Gill S, et al. Barriers to the use of disease-modifying treatments in sickle cell disease: a survey of patients and caregivers. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 2258. Accessed December 19, 2022. https://ash.confex.com/ash/2022/webprogram/Paper170881.html

3. Inserro A. Voxelotor for sickle cell disease wins FDA nod for patients as young as 4. The American Journal of Managed Care®. December 17, 2021. Accessed December 16, 2022. https://www.ajmc.com/view/voxelotor-for-sickle-cell-disease-wins-fda-nod-for-patients-as-young-as-4

4. Actigraphy improvement with voxelotor (ActIVe) study. ClinicalTrials.gov. Updated April 22, 2022.Accessed December 16, 2022. https://clinicaltrials.gov/ct2/show/NCT04400487

5. Shah N, Brown C, Andemarian B, et al. Active study: impact of voxelotor on sleep quality, physical activity, and patient-reported outcomes. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 2375. Accessed December 19, 2022. https://ash.confex.com/ash/2022/webprogram/Paper168317.html

6. Pfizer completes acquisition of Global Blood Therapeutics. News release. Pfizer. October 5, 2022. Accessed December 16, 2022. https://bit.ly/3hAW0I7

7. Pfizer to acquire Global Blood Therapeutics for $5.4 billion to enhance presence in rare hematology. News release. Pfizer. August 8, 2022. Accessed December 19, 2022. https://bit.ly/3G9DVdy

8. Study to evaluate the effect of voxelotor administered orally to patients with sickle cell disease (GBT_HOPE) (GBT_HOPE). ClinicalTrials.gov. Updated January 7, 2021. Accessed December 19, 2022. https://clinicaltrials.gov/ct2/show/NCT03036813

9. Study to evaluate the effect of gbt440 in pediatrics with sickle cell disease (HOPE Kids). ClinicalTrials.gov. Updated August 30, 2022. Accessed December 19, 2022.https://clinicaltrials.gov/ct2/show/NCT02850406

10. GBT initiates phase 2/3 clinical trial of GBT601 in Patients with sickle cell disease. News release. FDA. June 29, 2022. Accessed December 16, 2022. https://ir.gbt.com/news-releases/news-release-details/gbt-initiates-phase-23-clinical-trial-gbt601-patients-sickle

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