Ash 2022 – the sickle cell race hots up
Sangamo emulates Editas, while Crispr/Vertex and Bluebird add weight to their ambitions.
Previous data with Sangamo’s sickle cell disease gene editing contender BIVV003 were not enough to keep the group’s erstwhile partner Sanofi interested. Sangamo will now hope that it can become a contender here with promising – but very early – data from the first patient treated using a new manufacturing process.
A poster unveiled at Ash on Saturday showed that this patient had foetal haemoglobin levels of 45% at 26 weeks, making BIVV003 look similar to Editas’s EDIT-301, which produced similar data in a single patient last week. Meanwhile, the leading players in genetic medicines for sickle cell, Crispr/Vertex and Bluebird, also featured in oral presentations at this year’s Ash.
Both Sangamo’s BIVV003 and Editas’s EDIT-301 are designed to increase foetal haemoglobin to compensate for the defective haemoglobin found in sickle cell disease; Crispr and Vertex’s exa-cel has the same aim. Although these are all gene-edited projects they work differently: BIVV003 employs zinc finger nucleases, while EDIT-301 and exa-cel are Crispr-edited assets, but use different nucleases, AsCas12a and Cas9 respectively.
Last year at Ash Sangamo reported data with BIVV003 in four patients that looked decent – but not quite as good as results seen with exa-cel (Ash 2021 – Sangamo and Sanofi enter the sickle cell gene editing fray, December 13, 2021). Then in January Sanofi ended its partnership with Sangamo.
This year’s meeting featured longer-term data on the four BIVV003 patients. More importantly, the poster also included a first look at a new manufacturing process that, Sangamo hopes, could improve efficacy.
As well as the foetal haemoglobin finding, the subject using the BIVV003's new manufacturing process has not had any vaso-occlusive crises. It is probably too soon to read much into this given that the patient has only been followed for around six months.
More patients needed
Sangamo will need to replicate these findings in more patients before BIVV003 can be considered a contender – something that Richard Boismenu, a development programme leader at Sangamo, conceded when he spoke to Evaluate Vantage at the Ash meeting.
He maintained that Sanofi had walked away from the deal because it had wanted to focus on allogeneic, rather than autologous therapies like BIVV003.
An unavoidable fact, though, is that Sangamo is behind in a crowded space that could soon be sewn up by Bluebird and Crispr/Vertex.
This is a criticism that could also be levelled at Editas, which last week reported its early data from the Ruby trial of EDIT-301 separately from Ash. The first patient treated saw foetal haemoglobin levels of 45%, and there were no vaso-occlusive crises in two patients followed for five and 1.5 months.
| Cross-trial comparison of selected sickle cell projects | ||||||
|---|---|---|---|---|---|---|
| Project | Company/ies | Description | Trial | Modified Hb levels | VOCs | Source |
| Exagamglogene autotemcel (exa-cel, CTX001) | Crispr/Vertex | Crispr/Cas9 gene-edited cell therapy targeting BCL11A | Climb SCD-121 | Mean 43% at 12 mth in 9 pts | 0 | EHA & Ash 2022 presentation |
| Lovo-cel | Bluebird | Lentiviral gene therapy that produces anti-sickling Hb, HbAT87Q | HGB-206 study | Mean 45% at 24 mth in 16 pts | 1 | Ash 2022 presentation |
| BIVV003 (SAR445136) | Sangamo | Zinc finger nuclease gene-edited cell therapy targeting BCL11A | Precizn-1 | 11-40% in 4 pts with original manufacturing process; 45% in 1 pt with new manufacturing process | 2 (in 1 pt on original manuf process) | Ash 2022 poster |
| OTQ923 (HIX763) | Intellia/Novartis | Crispr/Cas9 gene-edited cell therapy targeting BCL11A | Ph1/2 | 16-22% in 2 pts | 0 | Ash 2022 abstract |
| EDIT-301 | Editas | CRISPR/Cas12a gene-edited cell therapy targeting beta-globin | Ruby | 45% in 1 pt | 0 | Company presentation, Dec 6 2022 |
| Note: all projects except Lovo-cel aim to increase foetal haemoglobin. Source: company presentations & Ash 2022. | ||||||
The leader in the space is arguably exa-cel; Crispr and Vertex have started a rolling application with the FDA, set to be completed in the first quarter of next year.
The update at Ash on Saturday concerned the same data presented at the EHA meeting in June (EHA 2022 – Crispr still looks bloody good, June 13, 2022).
One concern raised at the time was apparently waning haemoglobin levels, although Dr Haydar Frangoul of the Sarah Cannon Research Institute said during his Ash presentation that there was not enough data to show that this was occurring. “We have not seen any signal to show we’re losing efficacy of the treatment,” he said.
Bluebird reassures
Meanwhile, Bluebird’s lovo-cel is not too far behind, with an FDA filing due in the first quarter. This works slightly differently, being a gene therapy that aims to increase levels of an anti-sickling haemoglobin, HbAT87Q.
Attendees saw fuller data from part C of the HGB-206 trial of lovo-cel. Among 32 evaluable patients, only one had a severe vaso-occlusive event following lovo-cel infusion – one event among 29 patients had been detailed in the abstract.
The main focus of the presentation was the two patients – one adult and one child – who suffered anaemia, a side effect that had previously raised concerns about myelodysplastic syndrome.
Presenting the data, Dr Mark Walters of UCSF Benioff Children's Hospitals seemed unconcerned, saying: “The evidence doesn’t support an emerging MDS or malignant process.”
Lovo-cel is still on partial clinical hold in patients under 18, however. With the sickle cell pipeline behind Bluebird maturing, investors will want to see this lifted as soon as possible.
Source: Dr Mark Walters & Ash
