CRISPR-Cas9 Edited Therapy OTQ923 Displays Early Promise for Sickle Cell Disease

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In a small sample of patients, the CRISPR–Cas9–edited CD34+ hematopoietic stem- and progenitor-cell therapy showed expected safety while inducing red cell fetal hemoglobin.

James LaBelle, MD, PhD, an associate professor of pediatrics and the director of the Pediatric Stem Cell and Cellular Therapy Program at UChicago Medicine and Comer Children’s Hospital

James LaBelle, MD, PhD

Data from a phase 1/2 trial (NCT04443907) in individuals with severe complications of sickle cell disease (SCD) suggest that treatment with OTQ923, a CRISPR–Cas9–edited CD34+ hematopoietic stem- and progenitor-cell (HSPC) agent developed by Novartis, is able to effectively induce red cell fetal hemoglobin.1,2 Additionally, signs of clinical improvement in disease severity were observed in this small cohort effort.1

This study included 3 individuals (referred to as Participants 1-3) who were treated with autologous OTQ923 after myeloablative conditioning and followed for 6 to 18 months. All told, each of these individuals had engraftment stable induction of fetal hemoglobin at the end of follow-up (percentage of total hemoglobin, 19% to 26.8%) and broad distribution of fetal hemoglobin in red cells (percentage of red cells, 697.7% to 87.8%). Several adverse events (AEs) were observed, but the investigators deemed them to be related to either myeloablative busulfan conditioning or underlying SCD, and unrelated to OTQ923.

Study author James LaBelle, MD, PhD, and colleagues noted that SCD manifestations were reported to have decreased after administration as well, though all 3 participants experienced at least 1 SCD-related event. Participant 1 had a vaso-occlusive crisis linked to back and leg pain that acute chest syndrome 17 months post infusion; Participant 2 had leg pain associated with a vaso-occlusive crisis at 12 months post infusion; Participant 3 also had hip and lower-back pain associated with a vaso-occlusive crisis 9 months post infusion. Notably, participants 1 and 2 were admitted to the hospital for the management of pain episodes, and all 3 continued to have focal intermittent episodic pain in their hips and lower legs.

“The biggest take-home message is that there are now more potentially curative therapies for sickle cell disease than ever before that lie outside of using someone else’s stem cells, which can bring a host of other complications,” LaBelle, an associate professor of pediatrics and the director of the Pediatric Stem Cell and Cellular Therapy Program at UChicago Medicine and Comer Children’s Hospital, said in a statement.2 “Especially in the last 10 years, we’ve learned about what to do and what not to do when treating these patients. There’s been a great deal of effort towards offering patients different types of transplants with decreased toxicities, and now gene therapy rounds out the set of available treatments, so every patient with sickle cell disease can get some sort of curative therapy if needed. At UChicago Medicine, we’ve built infrastructure to support new approaches to sickle cell disease treatment and to bring additional gene therapies for other diseases.”

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As of the data cutoff date of March 27, 2023, a total of 16 participants had consented to participate in the study, though only 3 had received OTQ923. A partial dose of OTQ923 had been manufactured but not yet infused in 4 other participants, and the remaining 9 participants were found to be ineligible, withdrew, or had not started apheresis.

To summarize the clinical outcomes of the 3 individuals for whom data were available:

Participant 1 (22-year-old man with the βSS genotype)

  • Baseline: Receiving hydroxyurea therapy and regular red-cell exchange transfusions for 6 years because of recurrent episodes of vaso-occlusive crisis at enrollment. He discontinued hydroxyurea 2 months before CD34+ cell mobilization while continuing to receive exchange transfusions. His last red-cell transfusion was 26 days post OTQ923 infusion.
  • Pre-OTQ923 infusion: Total hemoglobin level, 10.0 g/dL; fetal hemoglobin, 0.4%; F cells, 4.0%.
  • 12-18 months post infusion: Total hemoglobin level, 10.3 to 11.9 g/dL; fetal hemoglobin, 25.0% to 26.8%; F cells, 78.1% to 87.8%.

Participant 2 (21-year-old man with the βSS genotype)

  • Baseline: Had multiple episodes of vaso-occlusive crisis while receiving hydroxyurea, which was discontinued 4 months before CD34+ cell mobilization and collection. Monthly exchange red-cell transfusions were then initiated. His last red-cell transfusion was 17 days post OTQ923 infusion.
  • Pre-OTQ923 infusion: Total hemoglobin level, 7.6 g/dL (at screening evaluation, before the initiation of monthly red-cell transfusions); fetal hemoglobin, 4.2%; F cells, 20.4%.
  • 6-12 months post infusion: Total hemoglobin level, 10.1 to 11.5 g/dL (transient decrease to 8.6 g/dL after a total hip arthroplasty); fetal hemoglobin, 23.0% to 25.3%; F cells, 80.4% to 86.8%.

Participant 3 (24-year-old woman with the βSS genotype)

  • Baseline: Had frequent episodes of vaso-occlusive crises resulting in hospital admission, avascular necrosis of the hips, and iron overload. She discontinued hydroxyurea 8 months prior to the first CD34+ cell mobilization while continuing to receive monthly exchange transfusions. Her last red-cell transfusion was 19 days after OTQ923 infusion.
  • Pre-OTQ923 infusion: Total hemoglobin level, 8.3 g/dL (after initiation of exchange transfusions but before myeloablation); fetal hemoglobin, 1.4%; F cells, 6.2%.
  • 4-6 months post infusion: Total hemoglobin level, 10.5 g/dL; fetal hemoglobin, 19.0% to 23.4%; F cells, 69.7% to 85.6%.

About 100,000 Americans have SCD, with it affecting 1 in 365 Black babies and 1 in 16,300 Hispanic babies born in the United States, according to the Centers for Disease Control and Prevention.3 Previously, in preclinical experiments, LaBelle and colleagues wrote, “CD34+ HSPCs obtained from healthy donors and persons with SCD that were edited with CRISPR-Cas9 and gRNA-68 had sustained on-target editing with no off-target mutations and produced high levels of fetal hemoglobin after in vitro differentiation or xenotransplantation into immunodeficient mice.”

LaBelle et all explained that SCD is the result of a defect in the β-globin subunit of adult hemoglobin—sickle hemoglobin then polymerizes under hypoxic conditions, producing deformed red cells that hemolyze and causing vaso-occlusion, ultimately leading to organ damage and early death. Although, elevated fetal hemoglobin levels in red cells can protect against these complications, creating promise for OTQ923.

REFERENCES
1. Sharma A, Boelens JJ, Cancio M, et al. CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease. N Engl J Med. 2023;389:820-832. doi:10.1056/NEJMoa2215643
2. New study shows promising evidence for sickle cell gene therapy. News release. University of Chicago Medical Center. August 30, 2023. Accessed August 31, 2023. https://www.eurekalert.org/news-releases/999989
3. Data & Statistics on Sickle Cell Disease. CDC website. Reviewed July 6, 2023. Accessed August 31, 2023. https://www.cdc.gov/ncbddd/sicklecell/data.html
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