STOP-HAE: A Phase 3 Study of ADX-324 in HAE

Inclusion Criteria:

1. Age ≥18 years at the time of signing informed consent.

2. Provided written informed consent and any authorizations required by local law andbe willing to comply with all study requirements for the duration of the study.

3. Have a documented diagnosis of HAE-1/HAE-2 (Type I or II) based upon ALL of thefollowing (a, b, AND c):

4. Documented clinical history consistent with HAE (SC or mucosal, non-pruriticswelling episodes without accompanying urticaria).

5. Diagnostic testing (historical documentation or during Screening, with optionof one repeat test) that confirms 2 of the following:

• C1-INH antigen level <50% the lower limit of normal (LLN).
• C1-INH functional level <50% LLN.
• C1-INH function ≥50% but ≤60% and a pathogenic mutation in the SERPING1gene.
• Complement factor C4 level below the LLN.

3. Have at least one of the following:

• Age ≤30 years at reported HAE onset.
• A family history consistent with HAE-1/HAE-2.
• Complement component 1q within the normal range.

4. Experienced ≥1 Investigator-confirmed HAE attack in the first 4 weeks of Screeningor ≥2 Investigator-confirmed HAE attacks in 8 weeks of Screening.

5. Have access to, and the ability to use, at least one acute HAE therapy to treat HAEattacks (eg, plasma-derived or recombinant C1-INH concentrate or a BK2-receptorantagonist) that has previously been shown to be effective for the participant.

6. Participants must be deemed medically appropriate for on-demand treatment as thesole medicinal management for their HAE during the study, per Investigator.

7. Women of childbearing potential must have a negative serum pregnancy test duringScreening and a negative urine pregnancy test on Study Day 1 before study drugadministration and must agree to use acceptable contraceptive methods if engaged insexual activity of childbearing potential (refer to Section 13.2.2) from the time ofsigning the informed consent form (ICF) until the EOS Visit or 1 month after studydrug administration, whichever is longer.

Exclusion Criteria:

1. Concurrent diagnosis of another form of recurrent angioedema. Examples include, butare not limited to, acquired angioedema, HAE with normal C1-INH (previously known asHAE Type III), idiopathic angioedema, and recurrent angioedema associated withurticaria.

2. Any clinically significant medical history including, but not limited to,uncontrolled hypertension (defined as systolic blood pressure ≥160 mmHg or diastolicblood pressure ≥ 100 mmHg despite therapy), uncontrolled diabetes mellitus (HbA1c >9.0%), or current cardiovascular disease, including recent acute coronary syndrome (within the past 6 months), congestive heart failure (NYHA Class III or IV), andsignificant arrhythmias.

3. History of alcohol or drug abuse within the previous year prior to Screening, orcurrent evidence of substance dependence or abuse and/or self-reported alcoholicintake averaging >3 drinks/day.

4. Any clinically significant renal disease, including chronic kidney disease (CKD)Stage 3 or higher (eGFR < 60 mL/min/1.73 m²) or a history of nephrotic syndrome.

5. Any clinically significant hepatic disease, such as active hepatitis, cirrhosis,steatosis, or hepatic insufficiency (Child-Pugh Class B or C); Screening alanineaminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × upper limit ofnormal (ULN); or screening bilirubin direct >1.5 × ULN (unless due to Gilbert'ssyndrome). One retest is permitted.

6. A history of coagulopathies or bleeding diathesis.

7. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skinor carcinoma in situ of the cervix that has been successfully treated.

8. Active infection (viral, bacterial, fungal, or parasitic) requiring systemicantimicrobial therapy that will not be completed at least 5 days before Study Day 1,or active infection not requiring antimicrobial therapy that is moderate or severe (eg, cold, flu, or COVID-19) that has not resolved prior to Study Day 1.

9. Known HIV infection (per participant history and/or medical records) or positiveserology test for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV)during Screening.

10. Major surgery or significant traumatic injury within 30 days prior to signing theICF.

11. Exposure to any of the following LTP for HAE:

12. Chronic prophylaxis with C1-INH (CINRYZE, HAEGARDA, RUCONEST) within 2 weeksprior to Screening.

13. Chronic prophylaxis with berotralstat (ORLADEYO) within 3 weeks prior toScreening.

14. Chronic prophylaxis with lanadelumab (TAKHZYRO) within 8 weeks prior to theScreening.

15. Androgen use within 12 weeks prior to Screening.

16. Exposure to any of the following medications:

17. ACE inhibitors within 4 weeks prior to Screening.

18. New use of or increase in dose of estrogen-containing medications with systemicabsorption (such as oral contraceptives or hormonal replacement therapy) within 3 months prior to Screening. Participants on a stable dose ofestrogen-containing medications for ≥3 months prior to Screening are eligible.

19. Has a preplanned procedure during the study (Screening through EOS Visit) for whichuse of short-term HAE prophylaxis would be anticipated.

20. Received treatment with another investigational product or device within 4 weeks or 5 half-lives, whichever is longer, prior to Screening.

21. Received prior treatment with any RNA/DNA-based therapy for HAE (including ADX-324)or is intolerant of any prior RNA/DNA-based therapy for any condition, excludingvaccines.

22. Participant is breastfeeding.

23. Any condition or abnormal laboratory value, ECG finding, vital sign, or physicalexamination finding that, in the Investigator's opinion, would pose an unacceptablerisk to the participant if they participate in the study. One repeat laboratory testand ECG is permitted without consultation with the Sponsor. Persistent abnormalfindings of questionable clinical significance should be discussed with the Sponsor.