From ZZ to SZ to MZ to potentially MM! The New State of Play for RNA Editing in Alpha-1 Antitrypsin Disease

The last few days and weeks delivered critical datapoints in the race to develop RNA Editing oligonucleotides for the treatment of AATD.  The prize in the form of serving an inadequately addressed rare disease with low single digit hundred thousand ZZ patients in the US, Europe, and Japan is enormous, thus spurring the development of increasingly better RNA Editing candidates.  Capitalism at its best. 

Getting close to the RNA Editing endgame

The picture that emerges shows Wave Life Sciences leading the pack with a clinical profile that could match the less severe SZ genotype (in terms of serum AAT abundance).  This should provide protection against progression of lung (but not liver) disease.  It has an about 2 years headstart in clinical development over competitor AiRNA which has a more realistic shot at replicating the more protective MZ genotype based on comparative mouse studies; and another year over Korro Bio’s AATD encore KRRO-111.  If what they claim is true, they may be getting close to the endgame with near complete Z-correction (MM-like), in the process surpassing what genome editing can do as well.

WVE-006

Wave Life Sciences’  WVE-006 has been discussed a lot on this blog.  I feel like I am slowly getting a handle on the true efficacy of this compound in the clinic- which has been made difficult by the company not broadly providing total serum AAT values.  Instead, it relied on revealing isolated serum M-AAT, the percent reduction of Z-AAT, and somewhat meaningless mean max numbers for total AAT.  Somewhat meaningless, because AAT fluctuates and just capturing the maximum values ever observed clearly introduces a significant bias to the upside.  

Considering that their reported ‘mean max’ barely matches what they say their assay measures for the mean (not even mean max) in ZZ natural history (13.1uM), it cannot be concluded that WVE-006 will achieve protection from progression of lung disease as expected from a MZ-like genotype and will likewise not be potent against AAT liver disease.  Accordingly, the case study they report on where a subject experiences an acute response shows total (Z) AAT serum levels to be similar, if not higher pre-treatment.  So if we wanted to analogize, something more akin to introducing a SZ-type genotype into a ZZ carrier should be the expectation.

AIR-001

Privately-held, pure-play RNA Editing company AiRNA announced having dosed their first clinical trial subject with AIR-001 last month.  AIR-001 is also a GalNAc-conjugated oligonucleotide and its preclinical mouse results have just been presented at the annual ASGCT conference in Boston.

In the same NSG-piz mouse model that Wave Life Sciences is using, and for the same 10mg/kg biweekly subcutaneous dosing regime, AIR-001 appears to achieve somewhat increased levels of RNA editing which in turn translated to somewhat increased serum M-AAT fractions (both up from ~50% to 60%).  Based on the prolonged stability of AIR-001 in monkey over mouse livers, AiRNA predicts a dosing frequency every 2 or 3 months which would be an improvement from Wave’s potential monthly dosing.

AIR-001 is just preclinical and WVE-006 has cleared a number of clinical safety and efficacy hurdles.  Getting closer to having a true MZ-genotype impact could be a best case scenario for AIR-001.

KRRO-111

To rain on everybody’s parade, Korro Bio then PR’d stunning headline results for its new AATD RNA Editing candidate.  KRRO-111 is its GalNAc oligonucleotide version after its LNP-based KRRO-110 seemed to do nothing in the clinic and the company may have to climb a mountain of investor skepticism before they all come onboard.

Still, by reporting near complete Z-AAT elimination and almost full M-AAT reconstitution with repeat-dosing of 3mg/kg in mice, and at one third the dose of the competition at that, one truly has to wonder whether we are closing in on the endgame for RNA Editing in AATD: from ZZ to MM.  The numbers also sound to be better than a single-shot of genome editing ever will be.  Beam Therapeutics conservatively itself bills BEAM-302 as MZ, though I myself believe that based on the >9:1 serum M:Z ratio, they are approaching something more like MM.

Unlike many biotech investors right now which can be grouped into CRISPR haters and lovers, I myself welcome the emerging choice for AATD patients.  Let us not forget that as alveolar damage from too little alpha-1 antitrypsin is not reversible (liver fibrosis may be) and gradual suffocation is an awful way to die (trust me).  The true AATD medical endgame would therefore also involve treating ZZ carriers as early as possible, certainly before symptoms emerge.  A genome editor would have to have an LNP delivery safety profile such that a person in her early 20s could be routinely administered; an RNA Editor convenient and sufficiently tolerated such that a carrier would be willing to repeatedly inject himself despite having no symptoms.

Disclosure: I am currently long Beam Therapeutics and Korro Bio.  No position in Wave Life Sciences as I want to sit out the feedback they will receive from the FDA on the development path for WVE-006.  Not investment advice.

Wave Life Sciences Sets 30% RNA Editing Bar for AATD

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.

 BEAM-302 appears to check it all

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.

An Explanation for the Disconnect between Z-AAT Editing Efficiency and Alpha-1 Antitrypsin Output

The commonly stated goal of alpha-1 antitrypsin editing approaches in addressing AATD is to achieve 50% editing of the mutant Z-allele.  This is based on human genetics showing that MZ heterozygotes have a much reduced risk of developing liver and lung disease.  

It therefore baffled me that Beam Therapeutics reported a year ago serum AAT levels of only ~12.4uM at day 28 despite having achieved 75-85% ZàM conversion with a 60mg dose of BEAM-302.  This compares to ~15-19uM concentrations seen in MZ heterozygotes, that is people who have just 50% of their AAT alleles in the M state.  

Back of the napkin math would have predicted ~22-30uM AAT levels with 75% M alleles if there was a corresponding relationship between the fraction of M alleles and AAT output.

Beam Therapeutics now reports improved serum AAT levels

This week, Beam Therapeutics reported that one additional year into the clinical trial, mean serum AAT levels in the 60mg cohort have increased to 16.1uM.  This includes an additional 3 patients over the 2025 data cut who had higher baseline AAT levels compared to the initial cohort of n=3.  Curiously, the company did not show how serum AAT changed over time, and now I think they did so on purpose because they did not want to steal the thunder from a future conference presentation.

Z-AAT relief effect following genetic correction takes time

ZZ homozygotes carry a high risk of developing liver fibrosis and ultimately liver failure in their lifetime because of the accumulation of Z-AAT aggregates in hepatocytes and resultant cell stress.  Consequently, less AAT gets out into circulation.  Arrowhead Pharmaceuticals and Takeda are addressing the liver disease aspect of AATD by Z-AAT RNAi knockdown with fazirsiran and are now running an unexpectedly long 4 year study after initial findings indicated slower than expected clearance of AAT aggregates and subsequent amelioration of fibrosis.

It therefore is plausible that the reason why serum AAT level undershoot following BEAM-302 treatment compared to genetic expectations is due to some lag in normalizing AAT output in subjects where Z-AAT had caused stress to the liver for decades of life already.  The increase from the mean 12.4uM reported last year to now 16.1uM could be a reflection of hepatocytes clearing the aggregates to relief endoplasmic reticulum stress and grease the AAT export machinery.  

Alternatively, you would have to explain why the inferred mean for the last 3 subjects comes out at 19.8uM versus the 12.4uM for the first 3 subjects.  Of course, you could try and explain some of it with the differences in baseline AAT output (which actually could also reflect Z-AAT-related liver stress), or time-dependent AAT increases as a result of a competitive growth advantage of corrected hepatocytes, or differences in the way serum AAT was measured last year and this year (turbidimetry vs LC-MS), but none of them explain both the serum concentration undershoot versus genotype expectation and the apparent increase over time.

Be prepared to be pleasantly surprised as more data from the BEAM-302 program emerges.  Also be wary of out-of-context data from investigator-initiated trials of obscure genome editing compounds like the YOLT-202 copycat.  

Base Editor Beam Therapeutics Sets New Record in Alpha-1-Antitrypsin Correction Race

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.