Sickle cell anaemia - Emerging treatments

Exagamglogene autotemcel

Exagamglogene autotemcel is a one-time gene therapy that uses CRISPR-Cas9 gene editing technology to alter the patient's own haematopoietic stem cells to produce higher levels of fetal haemoglobin in red blood cells. CRISPR-Cas9 gene-editing is used to target the BCL11A gene, deleting a portion of the gene associated with stopping the production of fetal haemoglobin soon after birth. The edited cells are infused back into the patient as part of an autologous haematopoietic stem cell transplant.[97] Exagamglogene autotemcel is currently being evaluated in an ongoing phase 1/2/3 trial in patients with severe sickle cell disease.[98] In phase 3 of the trial, 29 of 30 patients (97%; 95% confidence interval 83 to 100) who received exagamglogene autotemcel (and had sufficient follow-up to be evaluated) were free from vaso-occlusive crises for at least 12 consecutive months (mean duration of freedom from vaso-occlusive crises: 22.4 months). Additional trials are ongoing.[99][100] The US Food and Drug Administration (USFDA) and the European Medicines Agency (EMA) have both approved exagamglogene autotemcel for the treatment of sickle cell disease in patients aged 12 years and older with recurrent vaso-occlusive crises. In the UK, exagamglogene autotemcel has been approved by the National Institute for Health and Care Excellence (NICE) for use in the National Health Service (NHS) in England for patients aged 12 years and older with severe sickle cell anaemia.[101]

Lovotibeglogene autotemcel

Lovotibeglogene autotemcel (formerly called LentiGlobin) is a one-time gene therapy that uses a modified virus (lentivirus vector) to insert functional copies of a modified form of the beta-globin gene into a patient's own haematopoietic stem cells. Once incorporated, the functional gene enables the patient's red blood cells to produce anti-sickling haemoglobin. A phase 1/2 trial of 35 patients treated with lovotibeglogene autotemcel showed resolution of severe vaso-occlusive events in 25 patients who could be evaluated (with at least 6 months of follow-up) compared with a median of 3.5 events per year in the 24 months before enrolment. Treatment resulted in increased total haemoglobin levels (from median 8.5 g/dL at baseline to over 11 g/dL from at 36 months after infusion). Anti-sickling haemoglobin was produced in most red blood cells and comprised at least 40% of total haemoglobin. Hemolysis markers were reduced.[105] One phase 3 trial in adults and children with sickle cell disease is ongoing.[106] The FDA has approved lovotibeglogene autotemcel for the treatment of sickle cell disease in patients aged 12 years and older with recurrent vaso-occlusive crises.

IMR-687

IMR-687 is an orally administered, selective phosphodiesterase-9 (PDE-9) inhibitor. It increases fetal haemoglobin in erythroid cells.[107] One phase 2b, randomised, double-blind, placebo-controlled, multicentre study of subjects with sickle cell disease is ongoing.[108] IMR-687 has been granted orphan drug designation, rare paediatric designation, and fast track designation by the FDA.

Mitapivat

Mitapivat, a novel first-in-class pyruvate kinase activator, has been granted orphan drug designation by the US Food and Drug Administration for the treatment of sickle cell disease. Recruitment for a phase 2/3 trial is underway to assess the efficacy and safety of mitapivat in participants with sickle cell disease.[109] Mitapivat was previously approved by the FDA and European Medicines Agency for pyruvate kinase deficiency after meeting primary and secondary endpoints in phase 3 trials.[110]