Wave Life Sciences (here) and Beam Therapeutics (and here) just presented important updates on their alpha-1 antitrypsin disease (AATD) programs at the American Thoracic Society 2026 meeting in Orlando. Based on the latest disclosures, it is now possible to derive a reasonably robust estimate of not only the relative potencies of the competing product candidates (RNA editing WVE-006 and DNA base editing BEAM-302), but also the absolute editing efficiency for WVE-006, the industry’s lead RNA editing agent.
30%
RNA editing for 200mg biweekly
Taking into
account that misfolded mutant Z-AAT is less efficiently exported from
hepatocytes than wildtype M-AAT, 1.8-fold difference based on Wave’s estimate,
and deriving the mean serum AAT values from the spaghetti plots instead of
going with the mean individual max values Wave highlights when it presents
absolute numbers, the actual A-to-I editing efficiency in hepatocytes lies
between 25-30% at steady-state when WVE-006 is given every other week.
To be sure,
this is an excellent value for the first clinical RNA editing candidate and I
expect to see much less when ProQR will present its first clinical target
engagement data over the next month.
Nevertheless, given that the RNA editing competition, especially Korro,
now claim much higher (preclinical) editing values for alpha-1, Wave may have a hard time
competing in the long-term with WVE-006 and should develop a more potent
next-gen candidate alongside WVE-006.
30% editing
puts WVE-006 more into the range of the SZ genotype (instead of the stated MZ
goal). SZ is still significantly less pathogenic than ZZ and now appears to be Wave's newly stated goal. However, it should be inadequate when
addressing the liver manifestation of AATD, especially if treatment were to be
started at F2 fibrosis stage or later.
By
contrast, one-time DNA base editing competitor BEAM-302 has a ~3x higher
editing efficiency than WVE-006, and a pristine safety profile. There is minor transient and very mild grade 1 liver enzyme elevations at
the go-forward 60mg dose, but nothing really of concern, especially at later timepoints. This not only
means that it addresses the lung manifestation of the disease, also
demonstrated by showing for the first time a near total suppression of
neutrophil elastase activity in the clinic, but with a ~85% Z-AAT knockdown likely also
liver disease. Reversing existing liver disease, as indicated by Fazirsiran (see below), is a slower process, but this is as close to a cure you can get for AATD, if not an outright cure if BEAM-302 were to be given in early adulthood.
It has to
be said that an 85% DNA base editing knockdown is not equivalent to a similar
knockdown value obtained with an RNAi medicine as BEAM-302 works digitally at the individual hepatocyte level versus a more uniform gene suppression expected for an RNA agent like Arrowhead's/Takeda's Fazirsiran (note: Fazirsiran’s knockdown is closer to 93% for 200mg). The digital nature of DNA base editing might actually work in favor of DNA editing as the lower doses
show how corrected hepatocytes start replacing diseased ones over time.
Beam
Therapeutics now needs to finish dosing an additional 50 subjects at 60mg,
mainly to beef up the safety database, before it can submit 302 for
accelerated approval. Wave Life Sciences by contrast needs to carefully consider how much it wants to invest in further developing
WVE-006 when its inhibinE candidate is
their most promising pipeline candidate with multiple possible applications and
development paths. FDA feedback expected
over the next month or two for 006 should provide more clarity.
