HIGH IMPACT – Wave Life Sciences hosted an investor call titled “Towards the Clinic: Spotlight on RNA Editing for AATD” to discuss their technology, preclinical results, and path forward for WVE-006, their mRNA editing treatment for patients with alpha-1 anti-trypsin deficiency (A1ATD).

On the call: Dr. Paul Bolno (CEO), Dr. Paloma Giangrande (VP, WVE-006 Program Lead), Dr. Kyle Hogarth (U. of Chicago), Dr. Chandra Vargeese (CTO)

  • Reiterated the science behind RNA editing using AIMers, which incorporate A-to-I editing oligonucleotides using endogenous ADAR enzymes
  • WVE-006 is a GalNAc conjugated AIMer which corrects the mutation in the SERPINA1 Z allele which most frequently causes A1ATD (transforming from Z allele to M allele). This approach should treat both the liver damage that results from AAT protein aggregation in the liver as well as lung damage that results from a lack of AAT in the lungs.
  • Emphasized that an editing efficiency of ~50% would convert Pi*ZZ phenotype into Pi*MZ phenotype, which carries much lower risk of emphysema and liver disease
  • Preclinical data for WVE-006:
    • M-AAT levels increase in dose dependent manner in human hepatocytes

    • WVE-006 leads to 7-fold increase in circulating AAT levels

    • WVE-006 leads to restoration of confirmed, wild-type M-AAT protein in serum

    • Restored M-AAT is functional, leading to increased serum neutrophil elastase inhibition

    • WVE-006 (pre-optimization) alleviates aggregation of Z-AAT and inflammation in liver

    • AIMer-directed editing is highly specific in mice

  • Next Steps:
    • Phase 1/2 clinical trial is currently being planned
    • The trial will occur in a single-ascending dose phase in healthy volunteers then Pi*ZZ patients followed by a multiple-ascending dose phase in Pi*ZZ patients.
    • Primary outcomes include safety, tolerability, PK, and changes in relevant biomarkers, including serum AAT
    • Wave expects to submit the CTA for this trial in 2023
  • Dr. Kyle Hogarth of the University of Chicago provided a clinical perspective on A1ATD, briefly discussing his opinions on the current and future treatment landscape:
    • Augmentation therapy does provide benefit to patients with emphysema but requires once weekly IV of very expensive product
    • Recombinant AAT being developed by InhibRx may be longer lasting, but will still require frequent IV. Currently unclear how much of the product makes it into the lungs
    • Inhaled AAT being developed by Kamada may not get AAT levels high enough, especially in patients who already have airflow obstruction in the lungs
    • The neutrophil elastase inhibitor being developed by Mereo is an exciting approach but is more likely an add-on therapy
    • Various RNAi/sRNA products in development offer a good approach for treating the liver disease aspect but could cause levels of circulating AAT to go down, which could cause or exacerbate lung damage
    • While gene therapy is a promising option, in his experience taking a straw poll with patients, he has witnessed that many patients have concerns with gene therapy, including questions about efficacy and off-target effects
    • Both of Vertex’s small molecule programs have been stopped
    • Emphasized that WVE-006 is a promising option because it can treat both the lung and liver manifestations of A1ATD. Since it does not cause permanent genetic changes, it likely has a benign safety profile.
  • Wave also presented on some future applications of the AIMer program
    • AIMers can also upregulate gene expression and modulate protein-protein interactions
    • Showed data upregulating an undisclosed liver target with “high unmet need”
    • Showed data that a delivery vehicle may not be needed to get high levels of delivery to CNS
    • In response to question, Wave discussed the potential to apply this technology to any loss-of-function caused disease, but more specifically in hepatocyte driven disease, liver disease, kidney disease, and CNS disease

inThought Analysis

Wave first announced WVE-006 during its Q2 2022 earnings presentation. This investor call expanded upon the pre-clinical data the company has already shown, but there is no new guidance about its development. CTA submission is scheduled for 2023.

The company brought in a KOL to provide expert opinion on the current treatment landscape for A1ATD. While the discussion was biased and heavily favored WVE-006, it provided insight into potential messaging and counter positioning that Wave will likely use for WVE-006. Emphasis will likely be on the potential of WVE-006 that it can be more potent than current treatments since it corrects the genetic mutation that causes both lung and liver disease. The ASO’s selectivity will also decrease risk as it does not cause permanent genetic change. This messaging may be meant to bolster ASO therapies and discredit gene therapies in development by tapping into anxieties patients have about the permanence of gene therapy especially if it does not work or causes side effects.


Source: Wave Life Science Investor Call