Ash 2021 – Sangamo and Sanofi enter the sickle cell gene editing fray

SAR445136 could take on Crispr and Vertex’s CTX001, but plenty of other groups have the same idea.

For a rare disorder, sickle cell disease has certainly had a lot of interest from biopharma. The latest groups to throw their hats into the ring are Sangamo and Sanofi, which presented promising data with their gene-edited candidate SAR445136 yesterday at Ash.

However, with only four patients’ worth of data, it is too soon to say whether SAR445136 could be a real contender. And the companies will be going up against not only Crispr and Vertex, whose CTX001 made a splash at last year’s Ash, but a host of other players developing gene-edited projects in sickle cell too.

Crispr vs zinc finger

SAR445136 works differently from CTX001: the former uses zinc finger nucleases to edit a patient’s own stem cells, while CTX001 is based on Crispr/Cas9 technology. However, both projects have the same ultimate goal: reducing the expression of BCL11A, a transcription factor that normally suppresses the production of foetal haemoglobin.

It is hoped that increasing levels of foetal haemoglobin could compensate for the defective haemoglobin found in sickle cell disease.

This approach seems to have legs. The phase 1/2 Precizn-1 study of SAR445136 found that, in the four patients who have received therapy so far, there was a drop in the number of vaso-occlusive crises, the pain events seen in sickle cell disease.

In the two years before SAR445136 infusion, the four patients had 44 VOCs between them; after treatment, only one VOC was seen.

All four patients also had an increase in the proportion of foetal haemoglobin relative to total haemoglobin levels. However, this was not uniformly impressive: the worst-performing patient on this metric had 14% foetal haemoglobin at six months; this is also the patient who experienced a VOC.

Haemoglobin fractionation following SAR445136 infusion

Source: Ash.

Based on the data available so far, and with the usual caution about comparing different trials, CTX001 appears to have a slight edge over SAR445136.

At the latest update, at the European Hematology Association meeting in June, seven patients receiving the Crispr/Vertex project remained free of VOCs, with follow-up as long as 22.4 months in one subject.

Cross-trial comparison of gene edited projects for sickle cell disease
Project SAR445136 (BIVV003) CTX001
Company/ies Sangamo/Sanofi Crispr/Vertex
Trial Precizn-1 (NCT03653247) Climb SCD-121 (NCT03745287)
N at latest update 4 7
VOCs 1 0
Total Hb (g/dl) 9.2-11.0* 9.7-14.9**
% HbF 14-39%* 40-50%**
*At month 6; **at month 4. Source: Ash 2021 & EHA 2021.

However, long-term data on more patients will be needed on both projects before any firm conclusions can be reached.

This also goes for others trying to gain a foothold in the disease, including Beam Therapeutics, which recently got clearance to start a US study of its first sickle cell project, BEAM-101. The group’s base-editing technology is designed to be a more precise version of Crispr/Cas9.

BEAM-101 is also intended to increase foetal haemoglobin, but the company has a preclinical project, BEAM-102, that works differently, converting sickling haemoglobin to a naturally occurring human haemoglobin variant, HbG Makassar.

Graphite Bio claims to go a step further and to correct the underlying genetic mutation that causes sickle cell disease.

Still, all of the projects listed below are autologous, ex vivo therapies that require stem cell transplantation and, therefore, harsh pre-conditioning regimens. This will likely see their use limited to the severely affected patients, even if they get to market. Given these considerations the space is starting to look very crowded.

Selected ex vivo gene-edited sickle cell projects in development
Project Company/ies Description  Status/trial details
CTX001 Crispr/Vertex Crispr/Cas9 gene-edited cell therapy targeting BCL11a Ph1/2 Climb SCD-121; filing planned late 2022
SAR445136 (BIVV003) Sangamo/Sanofi Zinc finger nuclease gene-edited cell therapy targeting BCL11a  Ph1/2 Precizn-1; data on 4 pts at Ash 2021
GPH101  Graphite Bio Homology-directed repair gene-edited cell therapy targeting underlying beta-globin mutation Ph1/2 Cedar; initial data due YE 2022
OTQ923 & HIX763 Intellia/Novartis Crispr/Cas9 gene-edited cell therapy targeting BCL11a Ph1/2
EDIT-301  Editas CRISPR/Cas12a gene-edited cell therapy targeting beta-globin to increase foetal haemoglobin Ph1/2
BEAM-101 Beam Therapeutics  Base-edited cell therapy promoting foetal haemoglobin Beacon-101; IND cleared Nov 2021
BEAM-102 Beam Therapeutics Base-edited cell therapy recreating HbG Makassar variant Preclinical
Source: Evaluate Pharma &

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