Ash 2022 preview – waiting for Editas

Data on the group’s sickle cell project do not feature in the regular abstracts, while Bluebird walks away from its short hairpin contender.

2022 promised to be a big year for sickle cell disease, and this year’s Ash meeting will see updated results on Crispr and Vertex’s already impressive exa-cel, more data on Bluebird’s lovo-cel, and results from a handful of patients treated with therapies from the likes of Sangamo and Novartis.

One group that does not feature in the regular abstracts is Editas, despite it promising both a presence at Ash and initial data on EDIT-301 in sickle cell disease. It is possible that Editas has bagged a coveted late-breaker slot; however, only two patients have been treated so far in the phase 1/2 Ruby trial. Editas had not responded to a question about its Ash presence at the time of publication.

Meanwhile, Bluebird Bio has told Evaluate Vantage that it is “winding down” its work on a short hairpin RNA project targeting BCL11A, which first came to prominence at Ash 2019. More data from an investigator-led pilot trial will feature at this year’s meeting, and an academic phase 2 study is now recruiting.

Race for the prize

This project was always well behind in the race to get a gene-based medicine approved for sickle cell disease, and Bluebird’s focus will now be on lovo-cel, which is vying with Crispr Therapeutics/Vertex’s exagamglogene autotemcel.

Exa-cel looks to be slightly ahead: Crispr is to start a rolling submission in the US this month, while Bluebird maintains that it is still on track to file lovo-cel in the first quarter, despite its partial clinical hold in under-18s following a case of anaemia. Bluebird said during its third-quarter results that it was still working to resolve this.

The Ash abstract on lovo-cel had some good news on this front: it details two cases of persistent anaemia in part C of the HGB-206 trial, but does not conclude that these were myelodysplastic syndrome. Worries over malignancies put the same study on a fairly short-lived hold in early 2021.

The FDA has shown that it is comfortable with the risk/benefit profile of this project, approving it as Zynteglo for beta-thalassaemia in August. Bluebird will have to hope that the agency has a similar attitude in sickle cell.

For Crispr, meanwhile, the main focus at Ash is on its allogeneic CD19 Car-T project CTX110, but the group will also have data on exa-cel in both sickle cell disease and beta-thalassaemia. The results in the abstract echo those presented at EHA in July, so investors will be looking for more patients and longer follow-up at Ash.

Selected Ash sickle cell and beta-thalassaemia abstracts
Project Description Company/ies Abstract Details
Lovo-cel Beta-globin gene therapy Bluebird 11 28 of 29 SCD pts had no VOCs in part C of ph1/2 HGB-206 study; 2 pts with persistent anaemia not classed as MDS
Exagamglogene autotemcel (exa-cel, CTX001) Ex vivo Crispr/Cas9 gene-edited therapy against BCL11A Crispr/Vertex 12 No VOCs in 31 pts in Climb SCD-121; same as EHA 2022
2137 42 of 44 pts in Climb Thal-111 transfusion free; same as EHA 2022
OTQ923 (HIX763) Crispr/Cas9 gene-edited cell therapy targeting BCL11A Intellia/Novartis 786 HbF levels of 16-22% in 2 SCD pts in ph1/2
BIVV003 (SAR445136) Zinc finger nuclease gene-edited cell therapy targeting BCL11A  Sangamo 2140 HbF levels of 12-41% in 4 SCD pts in Precizn-1; 5th subject treated with new manufacturing method
Zynteglo (beti-cel) Beta-globin gene therapy Bluebird 2348 Beta-thal, long-term outcomes
3665 Beta-thal, long-term patient-reported outcomes
ET-01 Crispr/Cas9 gene-edited cell therapy targeting BCL11A Edigene (China) 4778 HbF increase from 3-90g/l in 1 beta-thal pt in EDI-001*
BCL11A shRNA Short hairpin RNA targeting BCL11A Academic (ex-Bluebird) 4784 HbF levels of 21-42% in 7 SCD pts in ph1*
*Investigator-sponsored trial; HbF=foetal haemoglobin; SCD=sickle cell disease; VOC=vaso-occlusive crisis. Source: Ash.

Decent data with Sangamo’s sickle cell contender BIVV003 at last year’s Ash did not stop the group’s partner, Sanofi, from walking away in January. Sangamo is back this year with more results from the Precizn-1 trial, which is to include a first look at patients treated using a new manufacturing process.

Stifel analysts reckon that, to compete, BIVV003 will need to show “near-perfect elimination” of vaso-occlusive crises – something the project has not managed to do so far.  

Like exa-cel, BIVV003 is designed to reduce the expression of BCL11A, thereby increasing levels of foetal haemoglobin, which is thought to compensate for the defective haemoglobin found in beta-thalassaemia and sickle cell disease.

OTQ923, being developed by Novartis and Intellia, also harnesses this mechanism, and investors will get a first look at data on this project at Ash. The abstract, with a cut-off date of July, includes just two patients treated so far.

Some other prominent groups with ex vivo gene-edited sickle cell projects do not feature at Ash, however. One is the base-editing specialist Beam, which has yet to enrol the first patient into the Beacon trial of Beam-101; the group this week deprioritised its follow-on asset, Beam-102. 

Meanwhile, Graphite Bio had once been expecting proof-of-concept data this year with its lead project, nulabeglogene autogedtemcel (GPH101), but in March said this would not come until 2023. All eyes are now on Editas.

The Ash conference is due to take on December 10-13 in New Orleans, Louisiana.

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