One of the key themes of this year’s Ash meeting was the cautious progress finally being made against acute myeloid leukaemia, but the presentation of remarkable data from Pfizer’s SMO inhibitor glasdegib on Saturday flew under the radar of many analysts.
Other developments that might not have caught mainstream attention included insight into BCMA, now clearly the most promising CAR-T antigen of interest after CD19, and progress in understanding CAR-T relapse mechanisms. However, it is the glasdegib data that might have the most near-term relevance for industry R&D, given how little perceived importance this drug class has.
Glasdegib is an inhibitor of the SMO receptor. This approach, also known as Hedgehog pathway blocking, was once thought to have great potential, but only two such agents have reached the market, both for treating basal cell carcinoma: Roche/Curis’s Erivedge was approved in 2012, but sold just $174m last year, while Novartis’s Odomzo got the FDA green light last year.
The glasdegib data point to AML as an obvious use to investigate, and might give a boost to some other SMO inhibitor assets, including Novartis’s LEQ506/LDE255 and a preclinical project at Redx Pharma. Given its intractability AML could be a more lucrative use than basal cell carcinoma.
Pfizer’s open-label study, whose readout featured at Ash, recruited first-line AML as well as high-risk myelodysplastic syndrome patients, adding glasdegib on top of cytarabine. Median overall survival, one of three primary endpoints, strongly favoured glasdegib, with a highly impressive 49% reduction in risk of death and a p value of 0.002.
Remarkably this benefit in 132 patients was driven by the project’s performance in the 116 patients who had AML. Among these the overall response rate was 24.4% versus 5.4% for control, and median overall survival 8.3 versus 4.3 months (54% reduction in risk of death, p=0.0004).
If Pfizer takes this asset forward into a larger trial it could add to the hope of finally treating AML. Other Ash developments here included promising data with Seattle Genetics’ vadastuximab talirine, and expansion of the Leukemia & Lymphoma Society’s Beat AML Master trial (Ash – Precision AML trial adds pharma candidates to the mix, December 5, 2016).
The plasma cell disorder multiple myeloma always features heavily at Ash, and this year targeting the BCMA antigen was closely watched as a means of treating late-stage, relapsed patients.
Enthusiasm was driven largely by the presentation on the eve of Ash of data with Bluebird’s CAR-T project bb2121. At Ash itself the NCI’s Dr James Kochenderfer updated his own study of an anti-BCMA CAR, showing seven PRs and one CR in 18 patients, including a 100% response rate at the highest cell dose.
Penn’s Dr Adam Cohen presented the first clinical data of Novartis’s CART-BCMA, from an initial non-lymphodepleted nine-patient cohort in which remission rate was 44%, with an 89% rate of cytokine release syndrome and one dose-limiting toxicity. Two further cohorts will use varying cell doses plus chemo conditioning.
However, both groups reported relapses owing to complete or partial loss of the BCMA target. Separately, relapses with Juno’s CD22-directed CAR, including through “decrease in site density”, were detailed for the first time (Ash – Relapses spell more CAR-T uncertainty for Juno, December 3, 2016).
Thus, while it had earlier been suggested that only CD19 was particularly unstable, it is now clear that both of the next two most important antigens can also be “lost” on the target cell. For anti-CD19 CARs relapses have been put down to waning T cells, or antigen loss by splicing out of part of CD19 or by the cells switching lineage.
At Ash University of Pennsylvania's Dr Jos Melenhorst detailed a fourth resistance mechanism, whereby in one ALL patient the CAR construct had accidentally been transfected into a B cell. Expansion of this subclone of “CAR-B cells” was deemed to be responsible for the relapse as, for unknown reasons, they “flew under the CAR-T cell detection radar” despite retaining CD19 expression.
This raises the question of how many other CAR relapses might be caused by such a manufacturing error, and the fact that a single mistakenly transduced cell can give rise to a resistant clone gives industry another headache to contend with. There will no doubt be plenty to discuss at Ash 2017.