Bluebird bio will be presenting what is expected to be 6 months of follow up on their first sickle cell disease (SCD) patient this weekend at the European Hematology Association (EHA) conference. There is a lot of investor interest in the first data for SCD coming out using their LentiGlobin gene therapy approach. So here are some thoughts about what I might expect the data to look like at 6 months.
To catch up, here are my previous posts on bluebird's LentiGlobin in SCD before the EHA abstract release, and analysis after the abstract release.
My interpretation of bluebird's abstract including 4.5 months of follow up has changed slightly after further considering a comment by @Sharma1981N after my previous writeup. The comment was: Do you think much of the increase in %T87Q from one point to the next could be attributed to decreasing % of transfused RBCs?
I initially responded thinking in terms of the g/dl of T87Q, and that likely it had indeed gone up considerably from month 3 to month 4.5. I wasn't, however, thinking about the relative amount of T87Q coming from the patient's own blood and how that was tracking. This is probably what's actually important, because if the patient is no longer receiving transfusions, then their blood should be made up entirely of HbS, T87Q & some HbF. Here is a table from the abstract breaking down the relative amounts of T87Q, HbS, HbF, and importantly the last pRBC transfusion:
The Day +88 transfusion was presumably right before the 3 month follow up. At the 3 month follow up only 9.6% of total Hb came from T87Q, but only 14.7% came from HbS, with presumably the majority of remainder (HbA) from the transfused blood (>70%). At 4.5 month follow up, not having any transfusions since, the % T87Q and % HbS both rose, to 24% T87Q & 33% HbS (with 7.6% HbF).
When looking at it this way, the amount of T87Q hemoglobin as a proportion of the hemoglobin made by the patient only increased slightly more than HbS did. So, on the downside, this suggests the relative levels of T87Q aren't actually climbing as fast as it seemed like based on the 9.6% to 24% jump. Since we don't have HbF levels for the 3 month visit, if you take that out of the equation and assume the entirety of the blood came from HbS and T87Q, then T87Q only went up from 39.5% of patient hemoglobin at 3 months to 42% of patient hemoglobin at 4.5 months. So, on the downside, T87Q as a proportion of patient hemoglobin might not be increasing that quickly, and may not increase that much more from 4.5 months on. On the plus side, this suggests that the patient is already making greater than 35% T87Q as a percentage of their total hemoglobin. If we include the 4.5 month fetal hemoglobin HbF, then the combined T87Q+HbF% is already up to 49% (37% coming from T87Q & 12% coming from HbF), with just 51% HbS. This is considerably above the 30% T87Q+HbF threshold bluebird has touted as being potentially ameliorative of symptoms.
Here are charts illustrating the above:
The % changes as in the abstract (assumes all non HbS or T87Q is transfused blood):
Relative amounts of T87Q and HbS coming from patient's blood at 3 & 4.5 months:
Adding back in HbF levels (only have data at 4.5 months):
Briefly, my thoughts on what %T87Q (+HbF) would be likely to achieve a functional cure - the short answer is I don't think we can know for sure yet. I've previously voiced my concerns over making that direct comparison to the 30% amount seen in Hereditary Persistence of Fetal Hemoglobin (HPFH) patients - my main argument focusing on the relatively even distribution of HbF across all red blood cells in those patients, versus most likely heterogeneous T87Q expression in LentiGlobin treated patients' red blood cells. However, even if somewhat heterogeneous, 30% would likely be clinically meaningful based on the amount of HbF increase typically seen with hydroxyurea treatment. I will probably include a slightly more detailed version of my thoughts on what I think about targets for %T87Q in a post after the data is presented.
So, in summary, when looking at the reported %T87Q changes from 3 to 4.5 months as a proportion of total hemoglobin (either patient or donor), the percentage appears to be rising dramatically. However, if we just look at the relative amounts of T87Q to HbS, the relative T87Q amount is rising much more slowly. If we even assume that this relative amount does not increase much more, if the patient is completely weaned off blood transfusions, then they would already produce in the range of 40% T87Q as a percentage of their total hemoglobin, and maybe only 50% HbS. If the patient hasn't received a transfusion since Day +88, it could very well allow the reported %T87Q (from either patient or donor) to rise to near 40% by the 6 month readout expected to be presented this weekend. So what I will be looking for is not only the %T87Q as a proportion of total hemoglobin, but also how the relative amounts of T87Q and HbS have changed from 3 to 4.5 to 6 months. Maybe I'll be surprised and the relative amount will increase substantially from 4.5 to 6 months. There are surely a number of assumptions in the above analysis, but hopefully it gives a good ballpark sense of where things seem to be tracking. Any additional phenotypic data on the patient or red blood cell function will clearly be important too.
Edit: Here is an image to demonstrate what I mean about the relative T87Q amount compared to all hemoglobin, versus the relative T87Q amount compared to patient-derived hemoglobin: