Beam Therapeutics Inc. (Beam), announced recent business and pipeline updates, as well as third quarter 2021 financial results, on 8 of November. Beam announced that its Investigational New Drug (IND) application for BEAM-101 for the treatment of sickle cell disease was cleared by the U.S. Food and Drug Administration (FDA). BEAM-101, the company’s lead ex vivo base editing product candidate, is a patient-specific, autologous hematopoietic investigational cell therapy which incorporates base edits that mimic single nucleotide polymorphisms seen in individuals with hereditary persistence of fetal hemoglobin (HPFH) to potentially alleviate the effects of mutations causing sickle cell disease or beta-thalassemia. This is the first open IND for base editing technology, a next-generation form of CRISPR capable of making single base changes without creating double strand breaks in the DNA. Beam is preparing to initiate a Phase 1/2 clinical trial designed to assess the safety and efficacy of BEAM-101 for the treatment of sickle cell disease, which Beam refers to as the BEACON-101 trial. More info: Beam Therapeutics, press release.

Chiesi Global Rare Diseases, a business unit of Chiesi Farmaceutici S.p.A., an international research-focused healthcare Group (Chiesi Group), announced that Health Canada has approved FERRIPROX® (deferiprone) for the treatment of iron overload in patients with sickle cell disease (SCD) or other anemias. FERRIPROX® was previously approved in Canada for the treatment of iron overload in patients with thalassemia major when current chelation therapy is inadequate. The decision comes about five months after the FDA approved FERRIPROX® for the same indication in the U.S. and one month after its approval in Brazil. Read here for more information.

A new treatment, called Adakveo (crizanlizumab), is now available to treat patients with sickle cell disease (SCD) through the United Kingdom’s National Health Service (NHS). Adakveo will be available in England and Wales to eligible patients, 16 years and older, to help prevent recurrent sickle cell crises (pain episodes). It can be given as an add-on therapy to hydroxyurea/hydroxycarbamide (HU/HC) or as monotherapy in patients for whom HU/HC is inappropriate or inadequate. This is the first time in decades that a new therapy for SCD has been made available on the NHS. Read here for more information.

The U.S. Food and Drug Administration (FDA)  has accepted Global Blood Therapeutics’ (GBT’s) supplemental New Drug Application (sNDA) seeking accelerated approval for Oxbryta® (voxelotor) for the treatment of sickle cell disease (SCD) in children ages 4 to 11 years and its New Drug Application (NDA) seeking approval for a new age-appropriate dispersible tablet dosage form of Oxbryta suitable for pediatric patients (i.e., 300 mg grape flavoring tablets). Oxbryta is currently approved by the FDA in a tablet dosage form to treat SCD in patients age 12 years and older. Oxbryta is a first-in-class therapy that directly targets hemoglobin polymerization, the root cause of red blood cell sickling in SCD. For more information, read GBT press release here

GPH101 (Graphite Bio Inc.) is an investigational gene-editing autologous hematopoietic stem cell (HSC) therapy designed to directly correct the genetic mutation that causes sickle cell disease (SCD). Preclinical data presented at Sickle Cell Disease Association of America 49th Annual National Convention 2021 highlights the potential of GPH101 to correct the underlying disease-causing mutation to decrease production of sickle hemoglobin and restore the expression of normal adult hemoglobin with minimal off-targeting, thereby supporting the initiation of Graphite Bio’s Phase 1/2 CEDAR clinical trial to evaluate GPH101 in SCD. The company plans to enroll the first patient before the end of the year. Briefly, GPH101 has the potential to achieve over 60% of gene-corrected beta-globin alleles in vitro with a reduced off-target cleavage by 30-fold, and achieve long-term engraftment (16 weeks) of gene-corrected cells in vivo (NSG mice) with no evidence of genotoxicity, abnormal hematopoiesis, or tumorigenicity, including no detectable chromosomal translocations. In addition, the data showed that gene-corrected red blood cells went from producing 100% sickle hemoglobin to expressing more than 90% normal adult hemoglobin. A copy of the poster presentation is available here. For more information: Graphite Bio’s press release

We are excited to announce the first article by the ClinGen Hemoglobinopathy Variant Curation Expert Panel (https://www.clinicalgenome.org/affiliation/50052/), published in Human Mutation (DOI:10.1002/humu.24280), that discusses the process, challenges and considerations of specifying the ACMG/AMP guidelines for variants related to hemoglobinopathies. The ACMG/AMP guidelines comprise a series of generic criteria for the standardized interpretation and reporting of sequence variants across laboratories. Owing to the varying degrees of subjectivity and uncertainty allowed by these guidelines, the Clinical Genome Resource (ClinGen) assembles Variant Curation Expert Panels (VCEPs) to develop specifications for the ACMG/AMP framework. The ClinGen Hemoglobinopathy VCEP was created collaboratively between the ITHANET Portal (https://www.ithanet.eu/) and the Global Globin Network of the Human Variome Project (http://www.humanvariomeproject.org/gg2020/) for specifying the ACMG/AMP variant curation framework to evaluate all available evidence relevant to hemoglobinopathies and the globin genes, with the aim to standardize the curation and interpretation of variants in different conditions. The Hemoglobinopathy VCEP specifications were approved by ClinGen in April 2021 (Step 2 approval), which initiated the process of further validation and adaptation with known globin gene variants in a pilot study (toward Step 3 approval). The observations by the Hemoglobinopathy VCEP outlined in this article can help highlight the challenges generally encountered during variant curation and interpretation and during the specification of ACMG/AMP guidelines for future VCEPs.