Disease Roundup: Genomic Medicine Candidates for Sickle Cell Disease

This roundup was originally published on 30^th December 2021. It was updated on 20^th July 2022 to reflect further developments in the CRISPR medicine field for sickle cell disease.

Sickle cell disease (SCD) is a group of diseases that are characterised by defective adult haemoglobin, which belong to a larger family of autosomal-recessive blood disorders known as the haemoglobinopathies (See Fact Box).

A number of treatments exist to manage the symptoms and complications of SCD but none of these are curative. Hydroxyurea was the first medication to obtain FDA approval for SCD (1997). It is an anti-cancer agent that promotes the production of foetal haemoglobin by a poorly understood mechanism and is widely used today despite side effects. Other treatments include Endari (2017), which increases L-glutamine levels in the blood triggering a cascade of events that reduces oxidative stress in sickled cells, allowing them to retain some function, Oxbryta (2019), which prevents defective haemoglobin from aggregating, thus ameriolating the symptoms of SCD, and Adakveo (2019), a monoclonal antibody that blocks P-selectin, thus lessening the inflammation associated with SCD.

Gene editing provides new hopes for SCD patients

Fortunately for the millions of SCD sufferers worldwide, decades of research to unravel the genetic pathways involved in regulating haemoglobin production has opened doors for diverse gene-editing approaches that aim to cure the disease.

There are currently seven clinical-stage candidates in development, five of which aim to restore foetal haemoglobin (HbF) expression through gene editing of patient-derived cells, while the other two aim to tackle the root of disease by direcly repairing the underlying disease mutation.

1. Exa-cel (CTX001): Vertex Pharmaceuticals, US and CRISPR Therapeutics, U.S.

Exa-cel is co-developed by Vertex Pharmaceuticals and CRISPR Therapeutics as a single-dose curative treatment for severe sickle cell disease (SCD) and the related disease blood transfusion-dependent beta-thalassemia (TDT). Specifically, CRISPR-Cas9 is used to delete the BCL11A in a patient’s own haematopoietic stem cells (HSPCs) ex vivo, and the engineered cells are then transplanted back into the patient where they express HbF to restore healthy red blood cell levels.

The ongoing CLIMB-111 (safety and efficacy in TDT) and CLIMB-121 (safety and efficacy in SCD) trials were the first CRISPR gene-edited therapy trials to be sponsored by US-based companies, and the most recent clinical data revealed at the European Hematology Association (EHA) 2022 Hybrid Congress support the curative potential of exa-cel for people with TDT or severe SCD.

Overall, clinical data obtained from 75 patients with TDT (n = 44) or severe SCD (n = 31) with follow-up times ranging from 1.2 to 37.2 months after dosing continue to demonstrate that exa-cel has the potential to be a one-time functional cure. All 31 severe SCD patients whose disease involves recurrent vaso-occlusive crises (VOCs, see Fact Box)) were free of VOCs after exa-cel infusion through duration of follow-up, which ranged from 2.0 to 32.3 months. SCD patients also had mean HbF (as a proportion of total Hb) of approximately 40% by Month 4 and maintained thereafter. Safety data for exa-cel collected to date are generally consistent with myeloablative conditioning and autologous stem cell transplantation. Additional details on the clinical efficacy and safety data for exa-cel, as well as plans for paediatric testing, can be found in the company's press release.

Exa-cel is the most advanced clinical-stage gene-editing candidate for SCD and beta thalassemia to date, and it has so far been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. Food and Drug Administration (FDA) for TDT and SCD, as well as Orphan Drug Designation from the European Commission, and Priority Medicines (PRIME) designation from the European Medicines Agency (EMA), for both TDT and SCD.

2. BIVV003 (also known as SAR445136): Sanofi, France

BIVV003 is an ex vivo-engineered autologous HSPC therapy that is designed to express HbF through BCL11A disruption. In contrast to CTX001, BIVV003 is edited using a zinc finger nuclease (ZFN) mRNA that, once translated, targets the BCL11A locus. BIVV003 is developed using Californian Sangamo Therapeutics proprietary ZFN technology.

The candidate is being developed as a one-time intravenous treatment for severe SCD, and is currently undergoing evaluation in the Phase 1/2 PRECIZN-1 study for severe SCD, which is sponsored by Sanofi. The study will evaluate its safety, tolerability, and efficacy of autologous HSPC transplantation using BIVV003 in up to 8 adult patients. Patient participation in this trial is approximately 136 weeks, and enrolled subjects will be asked to participate in a separate long-term follow-up study to monitor the safety and efficacy of BIVV003 treatment for a total of 15 years post-transplant.

In March 2021, Sangamo Therapeutics announced that the European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) released details supporting the Orphan Designation of BIVV003. This decision was partially based on early clinical data from three patients that had 52 weeks, 13 weeks, and 29 days of follow-up, respectively. Preliminary proof-of-concept clinical data presented at the American Society of Hematology (ASH) Annual Meeting 2021 showed no treatment-related adverse events, increased total and foetal haemoglobin levels in all four treated patients, and no treated patients required blood transfusions post engraftment. Further details of that data can be found here.

In January 2022, Sangamo announced the transition of the BIVV003 (SAR445136) SCD programme from Sanofi to Sangamo. According to the same press release, the Phase 1/2 PRECIZN-1 study is expected to be completed as planned, with the final patients in the study expected to be dosed in the third quarter of 2022.

3. OTQ923 and HIX763: Novartis, Switzerland

Switzerland-based Novartis Pharmaceuticals initiated a first-in-patient, Phase 1/2, proof-of-concept study in 2020 to follow patients for two years after transplantation of one of two ex vivo CRISPR-edited autologous HSPC experimental therapies for SCD.

The experimental therapies are OTQ923 and HIX763, both of which are designed to reduce the biologic activity of the B-cell lymphoma/leukaemia 11A protein (BCL11A), increasing fetal haemoglobin (HbF) and reducing complications of SCD.

The study, which is open-label and non-randomised, will be split into 3 distinct sections that will individually assess the candidate therapies in adults and children. The first part of the study will include treatment of adults with OTQ923, the second part will include treatment of adults with HIX763, and the third part will include treatment of children 2-17 years old with either OTQ923 or HIX763.

OTQ923 and HIX763 are CRISPR-edited HSPCs that are developed using CRISPR-Cas9 RNA guides identified through a collaboration between Novartis and Intellia Therapeutics. The trial is currently in the recruitment stage for a total of 30 participants and the expected completion date is in November 2023.

4. EDIT-301: Editas Medicine, U.S.

EDIT-301 is being developed by Editas Medicine as an autologous CRISPR-edited cell therapy for the treatment of severe SCD. The new candidate will be assessed in the RUBY Phase 1/2 trial in 40 adult participants between the ages of 18 and 50 years.

EDIT-301 is the first experimental medicine developed using CRISPR-Cas12a gene-editing technology, and it is specifically edited using a CRISPR-Cas12a ribonucleoprotein to enhance the HBG1/2 promoter region in the beta-globin locus of patient-derived HPSCs. Naturally-occurring HbF-inducing mutations at the HBG1/2 region support the clinical relevance of using gene editing to enhance the HBG1/2 promoter, and this strategy has been shown to increase the red blood cell levels of HbF.

Editas presented data at the 25^th European Hematology Association meeting in 2020 demonstrating that red blood cells derived from EDIT-301 HSPCs exhibit a sustained in vivo increase in HbF in animal models. The same year, Editas obtained Rare Pediatric Disease Designation for EDIT-301 as a potentially best-in-class treatment for SCD in children from birth to 18 years. The company obtained FDA clearance to initiate the RUBY trial in January 2021. At the European Hematology Association Congress in June 2021, the company released pre-clinical data on EDIT-301 supporting the inititiation of the RUBY trial for severe SCD.

The single-arm, open-label, multicenter RUBY trial is actively recruiting, and the overall goal is to evaluate the efficacy, safety and tolerability of EDIT-301 in adults with severe SCD.

5. CRISPR_SCD001, University of California, U.S.

Mark Walters, MD at University of California, San Francisco Benioff Children's Hospital Oakland, in collaboration with University of California, Los Angeles and University of California, Berkeley is sponsoring a Phase 1/2 clinical trial for severe SCD in 9 participants between the ages of 12 and 35 years old.

During the study, the participants will receive a single intravenous transfusion of CRISPR_SCD001, which is an experimental therapy based on red blood cells that are CRISPR-edited to directly correct the mutation in the beta-globin gene responsible for SCD. Before transfusion, each partipicant will undergo a myeloablative conditioning procedure with the chemotherapeutic busulfan. Myeloablative conditioning destroys the cells in the bone marrow to prevent rejection of the transfused CRISPR_SCD001 therapy.

Recruitment is ongoing for this study, and the study completion date i.e. the date whereby data is available on the last study participant is set to May 28^th, 2026.

6. GPH101: Graphite Bio, U.S.

Graphite Bio, a spinout of Stanford University obtained FDA clearance in December 2020 for its lead CRISPR therapy candidate GPH101 to advance to clinical trials for severe SCD.

Similarly to CRISPR_SCD001, GPH101 is also designed to correct the HBB point mutation, and is anticipated to provide a permanent cure by targeting the root cause of disease and restoring completely normally-functioning red blood cells. The therapy is engineered using patient-derived HSPCs that are edited using Cas9-sgRNA gene-editing machinery and a DNA repair template, in a mechanism that essentially cuts the mutation out of the genome and replaces it with the correct sequence. Cas9-sgRNA is delivered through ribonucleoprotein protein (RNP) complexes while corrected DNA template delivery is achieved through an adeno-associated virus 6 (AAV6) vector.

A research report co-authored by Matthew Porteus MD PhD, of The California Institute for Regenerative Medicine and Stanford University, who oversaw the pre-clinical manufacturing and FDA-required safety studies for GPH101, demonstrated that AAV-mediated CRISPR-Cas9 correction of the HBB mutation improved SCD symptoms in a humanised mouse model for the disease.

The first patient was enroled in the CEDAR trial in November 2021, and at that time dosing was expected to be initiated in the first half of 2022. In March 2022, Graphite Bio announced in a business and financial report that as a result of the recent COVID-19 Omicron variant surge on patients, site resources, and operations, the company now plans to dose the first SCD patient with GPH101 in the second half of 2022, with initial proof-of-concept data anticipated in 2023. In the same press release, Graphite Bio announced that patient enrolment is now ongoing at multiple clinical sites, and that it expects to obtain initial proof-of-concept clinical data for GPH101 in SCD in 2023.

Graphite Bio announced in May 2022 that the FDA had granted Fast Track Designation to GPH101 for the treatment of sickle cell disease (SCD).

7. BEAM-101, Beam Therapeutics, U.S.

BEAM-101 is the first base-edited therapy candidate for a haemoglobinopathy, and is developed as a patient-specific, autologous HSPC therapy designed as a one-time treatment for SCD and TBT. Late last year, Beam Therapeutics announced that the U.S. FDA had cleared BEAM-101 for clinical evaluation as a treatment for SCD.

BEAM-101 cells are engineered ex vivo with an adenine base editor (ABE) that incorporates A → G base edits in the HBG1 and HBG2 gene promoters, which regulate the expression of HbF. These edits mimic the naturally-occurring HbF-inducing mutations observed in individuals that continue to produce foetal haemoglobin beyond infancy, leading to reactivation of HbF expression to compensate for the lack of adult haemoglobin in SCD. The BEAM-101 base-editing reagents are delivered to patient-derived haemopoetitic stem cells via electroporation. Results from animal studies reveal high levels of base editing and robust HbF induction after long-term in vivo engraftment with BEAM-101 cells.

According to a company press release, BEAM-101 is envisioned to be a one-time treatment for patients with SCD, and plans are underway to initiate the BEACON-101 trial, which will be a Phase 1/2 clinical trial to assess the safety and efficacy of BEAM-101 for the treatment of SCD.

We strive to keep you updated with clinical and pre-clinical news from the CRISPR Medicine field. For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.