Biotech Values

[iwfal]

CART vs DART thoughts - Thoughts/notes on bispecific antibodies (which I'll refer to generically as DART - homage to MGNX and the rhyme) vs CART. I've been meaning to get to a comparison for a while and the recent CART excitement (KITE, JUNO etc) provided a further impetus. There seems to be a general, often unstated, assumption recently that CART is just plain better. Stronger efficacy, lesser side effects. Cooler technology. While I won't argue with the latter (some of the T-cells being produced by CART companies are truly frankensteinian - with mods to 5 or more different genes), i was curious about the former.

I had hoped that by looking at the most advanced representatives of each group - CTL019 from JUNO and Blinatumomab from AMGN - it would be possible to distinguish some clear differences since both are anti-CD19 agents and both have some clinical data published. With the most significant overlap for pediatric ALL. Before that discussion however, some background:

1) Both agents suffer from significant and similar side effects. CNS events (seizures getting the most press, but others as well) and Cytokine Release Syndrome (CRS). And the CRS events are well accepted to be a function of tumor burden at start of treatment. (CNS events appear to be much more poorly understood). But it should be noted that JUNO seems to have historically been a little less forthcoming about this (e.g. The surprise earlier in the year when they announced the halt for treatment deaths - one for seizures)?

2) for both agents it is accepted (shows up in both blin and CTL019 papers) that the ratio of treatment units (mabs or tcells) vs blasts is an important predictor of response.

3) there are three generally accepted ways to deal with CRS symptoms. Dose ramping (both drugs do this). And if CRS does arise either Corticosteroids or anti-IL6. For whatever reason AMGN generally references using dexamethasone to mitigate CRS while JUNO generally seems to use tocilizumab (anti-IL6). (Note: JUNO seems to subscribe to a belief that corticosteroids dampen efficacy, but AMGN does not. See link of paper from an investigator on JUNO trials: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119809/ . Note that personally I suspect that using corticosteroids would, in fact, cause a damping of efficacy since corticosteroids are notoriously broad acting compared to IL-x inhibitors.)


Now for the comparison - such as it is. (On all of the above background items JUNO investigators and AMGN investigators seem to have taken different approaches.)

Some of the topline data released are:

Follicular lymphoma - CTL019 got 5/5 responses, 4/5 CRs; Blin got 10/12 responses.
DLBCL - CTL019 got 5/11 responses, 4/11 CRs; Blin got 6/11 responses, 4/11 CRs

Roughly the same apparent efficacy. But very small numbers and few details about patient population or protocol. The area of overlapping patient populations (to enable cross comparison) with the most published patients is relapsing or refractory B cell ALL. In particular pediatric since JUNO has focused on pediatric ALL. For this population the comparative results do not look as equal as the above DLBCL or Follicular Lymphoma.

For CTL019 in 39 pediatric patients with rr ALL 36 had a CR (92%). See link:
http://www.uphs.upenn.edu/news/News_Releases/2014/12/ctl019/
And i believe that the 39 pediatric patients described above are part of the same trials described in earlier and in more details in the following link: http://cancerres.aacrjournals.org/content/74/20_Supplement/PR06.short

For Blin:
A) in 34 pediatric patients with rr ALL 11 had CR (32%) - but this was a trial whose intent was to minimize side effects via dosing protocol. See link: https://ash.confex.com/ash/2013/webprogram/Paper59492.html
B) separately in 9 patients all post Stem Cell Transplant (tougher patients) there were 6 CRs. See link: http://www.haematologica.org/content/99/7/1212

However the problem is even within this patient population there are large differences in protocol. Essentially every JUNO trial forces pretreatment chemo to debulk, and AMGN does not (writeups of AMGN trials make explicit reference to debulking for specific patients - i.e. Making it clear it was not part of the standard protocol). And since there is moderately good evidence that the ratio of treatment units to blasts is important for efficacy this probably significantly weakens the efficacy numbers of Blin. In addition, as noted above, JUNO treats CRS with anti-IL6 whereas AMGN seems to favor broader corticosteroids. Finally JUNO just seems more willing to flirt with SAE. (E.g. The only known seizure death (a side effect of both drugs) is from JUNO.) In contrast AMGN ran the whole trial cited above just to find a dose regimen that would minimize side effects (and, presumably, efficacy) - succeeding with no (significant?) CRS at all in the final protocol. And in their recently released results from the adult ALL trial they had grade >=3 CRS down to 2 percent. (see link: http://www.amgen.com/media/media_pr_detail.jsp?year=2014&releaseID=1995941 )

All told i'd guess CTL019 is probably a little more potent than Blin. But nowhere near as much as the first look pediatric ALL numbers appear. And how that extrapolates to other CARTS and DARTs is far from clear since the remaining difference is probably not huge. A lot will depend on technology improvements, protocol optimization and combo therapies. Other notes:

1) one big question will remain the long term efficacy comparison - for which it is essentially impossible to tell now.

2) the kill switch being inserted into some CARTs may not fully address some SAE. i.e. Blin has a very short half life and yet still has significant seizure issues (although, to date, no one seems to have died of CNS issues related to Blin).

3) I'd suggest that once you get up to 90ish percent MRD- results for rr disease, which i think is probably achievable for both treatments (once they have figured out optimization) i would suggest that other factors (like long term survival) become more important.

Thoughts/comments welcome (of course). As usual.