With Bluebird’s accelerated filing plan in place, Zynteglo could be approved for sickle cell disease in 2022. If the dataset remains strong this should give the gene therapy a chance to compete against the more traditional drugs already on the market, Global Blood’s Oxbryta and Novartis’s Adakveo.
But Bluebird needs to look over its shoulder, too. Over the weekend the virtual European Society of Hematology meeting saw rival presentations from Crispr Therapeutics, Agios, Imara and Forma. Even Glycomimetics, which bombed in phase III last year, reckons it might have a path forward, though analysts seem unconvinced.
It is Crispr’s Vertex-partnered gene therapy CTX001 that is perhaps most intriguing, given that EvaluatePharma sellside consensus already sees it generating nearly $1bn of revenues by 2026, even though data on just one treated subject are available so far.
At EHA this was updated, the patient being said still to be free of vaso-occlusive crises (VOCs) nine months after receiving an infusion of the gene therapy. Up to 45 subjects are to be enrolled into this study and followed for two years, so it is clearly still early days for CTX001.
Reduction of VOCs is half of the new primary endpoint proposed by Bluebird on Friday for its potentially registrational study of Zynteglo.
Oral small molecule
Agios is pursuing a technically simpler approach with the oral small molecule mitapivat, and at EHA reported that five of eight evaluable sickle cell subjects given up to 50mg twice daily had achieved a haemoglobin increase of at least 1g/dl. Its trial aims to enrol 25 subjects, dosing some up to 100mg, according to an amended protocol.
However, Agios fell 7% on Friday as one VOC was disclosed as being a serious adverse event possibly related to treatment. Despite this Leerink analysts say they still hope that drugs with mitapivat’s mechanism, pyruvate kinase R activation, could lower VOCs if dosed chronically.
The mechanism is thought to reduce haemoglobin S polymerisation, and the same approach is being pursued by Forma Therapeutics’ lead asset, FT-4202. Forma’s EHA data were very early, however, detailing a median 4.7mmHg reduction in the point of sickling in three subjects 24 hours after a single dose; Forma’s trial also enrols healthy volunteers and has a placebo cohort, and only grade 1 adverse events have been seen so far.
Mitapivat carries 2026 sellside forecasts of $491m, but all in haemolytic anaemia, according to EvaluatePharma consensus. Since Forma is private FT-4202 does not attract sellside forecasts.
|Selected projects for sickle cell disease|
|Company||Project||Mechanism||Status for sickle cell disease||2026e indication sales ($m)|
|Global Blood||Oxbryta||HbS polymerisation inhibitor||Marketed||1,952|
|Bluebird||Zynteglo||HBB gene therapy||Group C of HGB-206 trial, mean 99.5% reduction in VOCs & ACS in 14 subjects||629|
|Crispr/Vertex||CTX001||Crispr gene therapy||Climb-121 trial, one subject VOC-free at 9mth||909|
|Agios||Mitapivat||Pyruvate kinase R activator||5/8 subjects showed ≥1g/dl increase in Hb, with one SAE||0|
|Forma||FT-4202||Pyruvate kinase R activator||Early data from 7 subjects||0|
|Imara (ex Lundbeck)||IMR-687||PDE9 inhibitor||Early data from 18 subjects||0|
|Glycomimetics/Pfizer||Rivipansel||Pan-selectin antagonist||Failed pivotal Reset trial||0|
|Source: EHA & EvaluatePharma.|
Imara, through the IMR-687 project licensed from Lundbeck, is pursuing yet another strategy for sickle cell, namely PDE9 inhibition, which it says prevents degradation of cGMP leading to reactivation of fetal haemoglobin.
Its study has evaluated 57 subjects for safety, and 18 have yielded efficacy results. These show a 1.7% mean increase in fetal haemoglobin from baseline at 25 weeks for a high dose, versus no increase for placebo or a low-dose cohort.
Imara also wants to combine IMR-687 with hydroxyurea, which is used to reduce the frequency of painful VOCs, and said so far the combo had shown no drug-drug interactions.
Finally, Glycomimetics is perhaps best remembered for its lead Pfizer-partnered sickle cell project, rivipansel, failing in the phase III Reset trial last year. However, it had until now revealed no data from Reset.
Its update is being presented not at EHA but at the Foundation for Sickle Cell Disease Research meeting in September, and this describes a post hoc analysis of Reset, looking at subjects with severe VOCs requiring hospitalisation and given rivipansel relatively early in their acute episode.
This, the company claims, shows a benefit for rivipansel in terms of time to readiness for discharge, the primary endpoint in Reset’s all-comers population. The full data will be of interest to some, but Stifel was dismissive, writing on Friday that it was “likely not worth pursuing rivipansel”.