Today Beam Therapeutics reported initial data for BEAM-302, a CRISPR-based base editor for the correction of the Z mutant form of alpha-1-antitrypsin (Z-AAT). With a mean total serum AAT of 12.4 micromolar (uM) at the high 60mg dose it surpasses the 10.8uM reported by Wave Life Sciences last October, with WVE-006 applying the transient, oligonucleotide-based RNA editing technology.
Importantly, ‘total’ serum AAT for BEAM-302 would include bystander-edited AAT as well as wildtype (M) AAT and Z-AAT. Both the biological activity and safety of bystander-edited AAT are controversial.
As discussed in my preview of the unfolding competitive AAT disease space, homozygous Z-AAT mutation leads to lung damage due to the inability of AAT to get out of the liver into circulation and up to 50% of such carriers eventually develop some kind of liver abnormalities as a result of Z-AAT accumulation in hepatocytes. Because Z-AAT may retain some protease inhibitor function, the amount of total serum AAT is considered a key biomarker in the development of AAT-based therapy for the lung disease with 10uM being the therapeutic threshold to beat. Personally, I would appreciate the actual biological AAT activity (numbers, not a general statement that total AAT was functional) in terms of elastase activity.
This, however, is just the beginning of the battle for the hearts and minds of AAT patients. Beam said that it planning further dose escalation beyond 60mg for what could be a one-time treatment. I would caution, however, that grade 1 liver enzyme elevations were seen ‘in some’ patients and only 3 patients had been given 60mg. Since Verve Therapeutics had run into a show-stopping LNP-related liver safety issue with a lipid formulation similar to the one being used by Beam Therapeutics and at similar, if not lower dose levels, I would wait for larger patient numbers before giving the all-clear in this regard.
In another bold move, Beam Therapeutics further wants to test 302 in AAT patients with mild to moderate liver disease. This population had been excluded so far for the noted safety considerations. While a -78% decline in circulating Z-AAT was noted today, the liver patient cohort will likely include biopsies which would allow to relate that number to the actual alpha-1-antitrypsin gene correction percentage…as well as to the amount and nature of bystander editing.
Meanwhile, Wave Life Sciences is not standing still and should be able to surpass the 12.4uM marker since they have only reported single dose results for the lowest patient cohort. A 200mg every other week cohort is dosing as is a single dose 400mg cohort per the latest update.
