Welcome to Biotechr

Biotechr is written by Dr. Robert Kruse (@RobertLKruse), who holds a PhD and is currently completing his MD. His research work focused on infectious disease and immunology. This blog is focused on analyzing the latest developments in biotechnologies being developed in academia and industry, with a particular focus on biomedical therapeutics. I hope that the posts are interesting and useful, and hope you join in the discussion with guest posts on the site!

Disclaimer: The thoughts on this blog are not intended as any investment advice regarding any companies that might be discussed, and represent my opinion and not the opinions of my employer. This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual.

Wednesday, May 20, 2015

Quick thoughts on bluebird pre-EHA abstract release

Just some quick thoughts before EHA abstracts get released tomorrow, where presumably we'll see some first data for LentiGlobin in sickle cell disease (SCD), as well as continued follow-up data in B-thalassemia. I'll also try to write up some impressions tomorrow if substantive data is released. To reiterate, none of this is intended as investment advice, more of a point to start a conversation on bluebird, and I do own some shares of bluebird currently. Generally, I am concerned that the massive run-up post-ASH data is a bit overdone, and might be pricing in basically perfect results, considering we're still relatively early in understanding the effects of bluebird's therapy. There are a few potential risks that I'll outline below:

Sickle Cell:
I co-authored an article on LentiGlobin in SCD with Zack @BioTerp, which can be found here. I basically feel the same way now as I did then, so, for a more in depth look at my feelings on this approach in SCD, definitely check that out. I expect the primary outcome we will see are the T87Q hemoglobin levels in the patient. My concerns are more that the therapy will take a longer time to produce maximal T87Q levels rather than never producing sufficient T87Q for clinical benefit. The reason it may take longer has more to do with the cell dose the first SCD patient received - 5.6 x 10^6 CD34+ cells. This is lower than B-thal subject 1102 (6.5 x 10^6 CD34+), who has taken a longer time than previous patients to achieve maximal levels of T87Q expression (also had lower VCN than other treated patients).
One reason for the low cell dose, and the reason all other treated SCD patients will also likely have lower cell doses is because SCD patients have to have CD34+ cells harvested from bone barrow as opposed to mobilized peripheral blood, and this typically gives lower cell yields. So if there is data in the abstract for only about 4+ months post-infusion, I would think there is a good chance the patient is not producing maximal T87Q levels yet.

A second point is the amount of maximal T87Q levels to eventually expect to see in this patient, or other patients with SCD. I expect this will be lower than what is seen in B-thal, but it would be difficult to accurately say how much. The reason I think we'll see lower total levels of T87Q expression, but even more so lower %T87Q relative to total hemoglobin, is due to the fact that in SCD, the patient has 2 copies of beta-globin (both with sickle mutations), whereas in B-thalassemia the patient only has 1 or 0 partially functional copies of beta-globin (βE in some of the first patients treated). Considering the LentiGlobin vector uses the transcriptional control elements of normal beta-globin, I would expect feedback within the cell will keep total levels of beta-globin relatively normal, and thus T87Q Hb has to compete against 2 expressing copies of HbS versus 1 or 0 copies of HbE. The sell-side analyst projections I see for %T87Q levels they are hoping to see (normally 30% T87Q) is considerably lower than what has been seen in B-thal patients so far, and I would say more reasonable with what one might expect.
For the reasons above, I don't think we'll see 70% T87Q in SCD patients dosed at ~1VCN, and definitely not this quickly. 30-50% T87Q I think we could see eventually, as the maximal levels, perhaps depending on the VCN of the infused product. I am also not as convinced that 30% T87Q is guaranteed to be functionally curative, or even equivalent to 30% HbF (fetal hemoglobin). My main concern here is that the fetal hemoglobin is spread more evenly throughout all the red blood cells, whereas probably only around 30% of stem cells will likely contain the T87Q vector, and make T87Q producing red blood cells. Now, there is data from "mixed chimerism" stem cell transplants in SCD that suggests a relatively small percentage (~10-30%) of normal stem cells can mediate complete protection, and that there is a survival advantage of non-sickling red blood cells, so that the vast majority (>90%) of red blood cells are actually normal, even if coming from only 30% of stem cells. So this may help a greater percentage of red blood cells to be T87Q protected, but I think it's more complicated than just saying 30% T87Q hemoglobin levels is the magic number that will be curative, and we'll have to see how it plays out clinically. I do think that these levels of T87Q would be very likely to be clinically beneficial, based on the relatively small increase in HbF seen in patients treated with hydroxyurea, but too early to say whether functionally curative or not.

In B-thal I expect to continue to see durable transfusion independence in the patients that are already independent. I think the durability will likely not be a big issue considering the durability of expression seen in subject 3 dosed with the original lentiviral T87Q hemoglobin expressing vector.

Considering the dose (CD34+ cell number) & quality (VCN) of the drug varies among patients, I would consider the whole clinical experience more like many n of 1 trials than a single trial with a single drug. Thus, I am a bit concerned that patients receiving lower VCN like subject 1104 (0.7 VCN) might produce lower maximal levels of T87Q than previous patients.

I would be more unsure if a patient with that low of a VCN were B0/B0, who would have very little/no hemoglobin of his/her own to rely on to supplement the T87Q produced, would reach transfusion independence within 12 months. Perhaps the lower VCN patients will still produce sufficient levels of T87Q for transfusion independence, but I think it's something to keep an eye on, and one should not assume yet that transfusion independence will be always be achieved in every patient.

So to summarize, my concerns have more to do with the market's reaction to the data, than with the long term viability of the approach. I still think, in the long run, LentiGlobin will be very effective in B-thalassemia, and is likely to have clinical benefit, although way too early to say if curative, in sickle cell disease as well. As an aside, I also feel their potential in the CAR-T field is under-appreciated, given some of the people involved in their program. We can only speculate on what their initial approaches will be, but I will definitely be interested in listening as we hopefully learn more about their CAR-T plans later this year and early next year.

Here is the follow-up post with my comments after the EHA abstract was released.

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