Can you give an overview of your practice?

Great. Can you give as an outline on the current SoC for liver disease associated with A1AD? And I guess the lung disease too if you’re familiar with that. 

It is my understanding that lung disease with A1AD is the major disease category. About what percentage of AATD patients suffer from lung disease vs liver disease, or both liver and lung?

Can you give me an idea how many A1AD liver disease patients end up needing a liver transplant, and how long that usually takes?

A1AD manifests as both liver and lung disease. Can you provide some insight as to how treatment with fazirsiran might affect the lung aspect of the disease?

On a high level, can you discuss the approaches from Arrowhead and Vertex, siRNAs vs correctors?

Discussing the open label phase 2 data, in the 200 mg cohorts, 9/12 patients had F2 or F3 fibrosis stages, and 5 on them were on augmentation therapy. Mutant Z-AAT was reduced in all patients, and all patients had decreased histologic globule burden. ALT concentrations were down, and fibrosis improved by one point in 9 of the 12 patients.

 I know this is small n and open label, but what are your thoughts on the efficacy shown here?

How do you think patients on existing augmentation therapy would affect efficacy, if at all?

Do you expect any variance in efficacy depending on fibrosis stage?

What are your thoughts on the safety profile shown? There was a variety, 4 TEAEs deems to be serious (viral mydocarditis associated with EBV infection, diverticulitis, dyspnea, vestibular neuronitis. Is there anything here you find concerning at this early glimpse?

So the SEQUOIA trial is expected to read out by the end of the year, they enrolled 40 patients, placebo controlled, seems inclusion data is the same the open label study, but they will be leaving out Fibrosis stage F4 patients. Primary endpoint is change from Baseline in Serum Z-AAT. What kind of results would you expect here vs placebo?

Given that there are no approved therapies for the A1AD liver disease, what do you envision would be an appropriate phase 3 design, including primary endpoint?

Let’s assume fazirsiran is the 1st drug approved in AATD, either lung or liver, how do you imagine it being used vs the current SoC?

How would you rate your enthusiasm about fazirsiran on a scale of 1-10, and you can you elaborate on why?

Are you familiar at all with the inhibrx drug at all? The recombination human AAT-Fc fusion protein with the potential to increase dosing range to 3 weeks?

Are there any other approaches to A1AD, whether liver or lung disease, that you find interesting and are following?

Is there anything I didn’t ask that you think I should have asked?