A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD)

Healthy volunteers and AATD patients will be randomized to receive a single intravenous injection of either ARC-AAT or Placebo in double-blind fashion. Up to thirteen cohorts (6 participants per cohort) will be enrolled. Participants in all cohorts will be confined to the clinical facility beginning on Day -1 with discharge on Day 2. Escalation to the next dose level will proceed until a participant experiences a dose-limiting toxicity (DLT) or there is achievement of pre-determined threshold reductions in AAT levels. Dosing in participants with AATD will commence based on pre-determined threshold reductions in AAT levels for healthy volunteers. For each participant, the duration of the study clinic visits is up to 11 weeks, from Screening to the End-of-Study examination. However, including a Day 90 Follow-Up telephone call, the maximum study duration is approximately 20 weeks.

• ARC-AAT Injection (Drug), also known as ARC-AAT: RNA interference-based, liver-targeted therapeutic
• Placebo (Other): 0.9 % normal saline
• Diphenhydramine (Drug): Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.

Primary outcomes

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), or Discontinuations Due to TEAEs [From the first dose of study treatment through Day 29 ± 1 day]: An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. TEAEs are defined as defined as AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. SAEs are defined as is an AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction.
• Number of Participants With Clinically Significant Treatment-Emergent Abnormalities in Laboratory Values [Day 1 through Day 29 ± 1 day]: Laboratory values collected include: hematology (haemoglobin, lymphocytes, neutrophils, platelets, white cell count, monocytes); biochemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, creatine kinase, creatinine, gamma-glutamyltransferase, fasting glucose, troponin I); coagulation parameters (fibrinogen, international normalized ratio); and C-reactive protein.
• Number of Participants With Clinically Significant Treatment-Emergent Abnormalities in Vital Signs, Electrocardiograms (ECGs), Pulmonary Function, Physical Findings, and Other Observations [Day 1 through Day 29 ± 1 day]: Values collected include: vital signs (clinically concerning or symptomatic treatment emergent changes in heart rate, systolic blood pressure, diastolic blood pressure, respiratory rate, or temperature); ECGs (clinically significant changes from baseline were observed for ventricular rate, RR interval, QRS duration, QT interval or QT interval corrected for heart rate using Fridericia's formula \[QTcF\]; treatment emergent clinically significant changes in ST segments, P wave or T wave morphology; cardiac telemetry monitoring); clinically significant abnormal physical examination findings; treatment emergent sensitivity to bee venom; pulmonary function (clinically significant worsening in spirometry parameters and carbon monoxide diffusing capacity of the lung for carbon monoxide \[DLCO\]).
• Pharmacokinetics of ARC-AAT: Maximum Observed Plasma Concentration (Cmax) for the Analytes AD00370 and ARC-Melittin-Like Peptide (MLP; Part A) [Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose]
• Pharmacokinetics of ARC-AAT: Time to Maximum Observed Concentration (Tmax) for the Analytes AD00370 and ARC-MLP (Part A) [Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose]
• Pharmacokinetics of ARC-AAT: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Time 24 Hours (AUC0-24) for the Analytes AD00370 and ARC-MLP (Part A) [Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose]
• Pharmacokinetics of ARC-AAT: Area Under the Plasma Concentration Versus Time Curve From From Zero to Infinity (AUCinf) for the Analytes AD00370 and ARC-MLP (Part A) [Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose]
• Pharmacokinetics of ARC-AAT: Terminal Elimination Rate Constant Obtained From the Slope of the Line (Kel) for the Analytes AD00370 and ARC-MLP (Part A) [Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose]
• Pharmacokinetics of ARC-AAT: Half-Life (t1/2) for the Analytes AD00370 and ARC-MLP (Part A) [Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose]
• Percentage Reduction From Baseline of AAT Up to Day 29 [Baseline, Days 3, 8, 15, 22 and 29]: Clinical assay for total serum AAT level was used for Part A. A quantitative measurement of AAT was used for Part B. A negative percent reduction indicates a percentage increase. Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1.

Secondary outcomes

• Number of Participants With AAT Reduction > 30% From Baseline (First Occurrence) [Baseline, Days 3, 8, 15, 22 and 29]: Data presents the study visit day upon which a participant had the first occurrence of AAT reduction of > 30% from Baseline, and the number of participants who had a > 30% reduction at any visit (overall). Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1.
• Maximum Percentage Reduction in Mean AAT (Nadir of Mean AAT) [Study Day for Nadir of Mean AAT: Day 8 (for Part B 2 mg/kg arm), Day 15 (for Part A 0.38 mg/kg, 2 mg/kg, 4 mg/ kg, Placebo arms; Part B 4 mg/kg, Placebo arms), Day 22 (Part A 3 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg arms), Day 29 (1 mg/kg, 8 mg/kg arms)]
• Number of Participants With a Return From Nadir AAT Blood Levels to Above Normal or Within 15% of Baseline in > 100 Days [Baseline, up to Day 29, and through 100 days of follow-up]: Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1.
• Mean Percentage Change in Circulating Blood Levels of Cytokines 2 Hours Post-Dose [Pre-dose, 2 hours post-dose]
• Mean Percentage Change in Circulating Blood Levels of Complement Factors 2 Hours Post-Dose [Pre-dose, 2 hours post-dose]

Sex: All, ages: 18 Years to 70 Years, accepts healthy volunteers

Inclusion Criteria:

(Part A - Healthy Volunteers)

* Male or female healthy volunteers 18-50 years of age
* Written informed consent
* Body mass index between 18.0 and 28.0 kg/m2
* 12-lead electrocardiogram (ECG) at Screening and pre-dose assessment with no clinically significant abnormalities
* Non-pregnant/non-nursing females
* Non-smoker for at least one year with current non-smoking status confirmed by urine cotinine
* Normal lung function (or not clinically significant per investigator assessment) based on spirometry and diffusion capacity of lung for carbon monoxide (DLCO) according to American Thoracic Society (ATS) - European Respiratory Society (ERS) criteria
* Highly effective, double barrier contraception (both male and female partners) during the study and for 3 months following the dose of ARC-AAT
* Willing and able to comply with all study assessments and adhere to protocol schedule
* Suitable venous access for blood sampling
* No abnormal finding of clinical relevance at screening
* Normal AAT level

(Part B-Patients) - As for Part A with the following exceptions:

* Male or female patients 18-70 years of age
* Confirmed diagnosis of homozygous alpha 1-protease inhibitor deficiency (PiZZ genotype) not receiving alpha-1 antitrypsin augmentation therapy for more than 4 weeks
* BMI between 18.0 and 35.0 kg/m2
* Non-smoker for at least three years with current non-smoking status confirmed by urine cotinine

Exclusion Criteria:

(Part A-Healthy Volunteers)

* Current regular smoker of cigarettes or cigars or was a regular smoker over the past 1 year
* Recent (within last 6 weeks) transfusion of fresh frozen plasma, platelets, or packed red blood cells, or anticipated need for transfusion during study
* Acute signs of hepatitis/other infection within 4 weeks of screening and/or baseline
* Concurrent anticoagulants
* Use of dietary and/or herbal supplements that can interfere with liver metabolism within 7 days of screening
* Use of any drugs known to induce or inhibit hepatic drug metabolism within 14 days prior to study treatment
* Depot injection/implant of any drug other than birth control within 3 months prior to study treatment
* Diagnosis of diabetes mellitus or history of glucose intolerance
* History of poorly controlled autoimmune disease or any history of autoimmune hepatitis
* Human immunodeficiency virus (HIV) infection
* Seropositive for hepatitis B virus (HBV) or hepatitis C virus (HCV), and/or history of delta virus hepatitis
* Uncontrolled hypertension (blood pressure > 150/100 mmHg)
* History of cardiac rhythm disturbances
* Family history of congenital long QT syndrome or unexplained sudden cardiac death
* Symptomatic heart failure (per New York Heart Association \[NYHA\] guidelines)
* Unstable angina, myocardial infarction, severe cardiovascular disease, transient ischemic attack (TIA) or cerebrovascular accident (CVA) within past 6 months
* History of malignancy within last 5 years except adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer.
* History of major surgery within 3 months of screening
* Regular use of alcohol within 1 month prior to screening (i.e., more than fourteen units of alcohol per week)
* Evidence of acute inflammation, sepsis or hemolysis or clinical evidence of lower respiratory tract infection
* Diagnosis of significant psychiatric disorder
* Use of illicit drugs (such as cocaine, phencyclidine \[PCP\] and crack) within 1 year prior to screening or positive urine drug screen
* History of allergy or hypersensitivity reaction to bee venom
* Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study
* Clinically significant history/presence of any gastrointestinal pathology, unresolved gastrointestinal symptoms, liver or kidney disease
* Other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs
* Any clinically significant history/presence of poorly controlled neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric, metabolic or other uncontrolled systemic disease
* Blood donation (500 mL) within 7 days prior to study treatment
* History of fever within 2 weeks of screening
* Concomitant medical/psychiatric condition or social situation that would affect compliance or result in additional safety risk
* Excessive exercise/physical activity within 3 days of screening or enrollment or planned during the study
* History of thromboembolic disease, stroke within 6 months of baseline, and/or concurrent anticoagulant medication(s)

(Part B-Patients) - As for Part A with the following exceptions:

* History of major surgery within 2 months of Screening
* Forced expiratory volume at one second (FEV1) at baseline < 60%
* AATD patients with liver elastography score > 11 at Screening

Participant flow

Outcome results

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), or Discontinuations Due to TEAEs (Primary), Number, participants: Part A: 0.38 mg/kg 2; Part A: 1.0 mg/kg 2; Part A: 2.0 mg/kg 2; Part A: 3.0 mg/kg 1; Part A: 4.0 mg/kg 3; Part A: 5.0 mg/kg 3; Part A: 6.0 mg/kg 3; Part A: 7.0 mg/kg 1; Part A: 8.0 mg/kg 3; Part A: Placebo 9; Part B: 2.0 mg/kg 3; Part B: 4.0 mg/kg 2; Part B: Placebo 4
• Number of Participants With Clinically Significant Treatment-Emergent Abnormalities in Laboratory Values (Primary), Number, participants: Part A: 0.38 mg/kg 1; Part A: 1.0 mg/kg 0; Part A: 2.0 mg/kg 0; Part A: 3.0 mg/kg 0; Part A: 4.0 mg/kg 0; Part A: 5.0 mg/kg 0; Part A: 6.0 mg/kg 0; Part A: 7.0 mg/kg 0; Part A: 8.0 mg/kg 0; Part A: Placebo 0; Part B: 2.0 mg/kg 0; Part B: 4.0 mg/kg 0; Part B: Placebo 0
• Number of Participants With Clinically Significant Treatment-Emergent Abnormalities in Vital Signs, Electrocardiograms (ECGs), Pulmonary Function, Physical Findings, and Other Observations (Primary), Number, participants: Part A: 0.38 mg/kg 0; Part A: 1.0 mg/kg 0; Part A: 2.0 mg/kg 0; Part A: 3.0 mg/kg 0; Part A: 4.0 mg/kg 0; Part A: 5.0 mg/kg 0; Part A: 6.0 mg/kg 0; Part A: 7.0 mg/kg 0; Part A: 8.0 mg/kg 0; Part A: Placebo 0; Part B: 2.0 mg/kg 0; Part B: 4.0 mg/kg 0; Part B: Placebo 0
• Pharmacokinetics of ARC-AAT: Maximum Observed Plasma Concentration (Cmax) for the Analytes AD00370 and ARC-Melittin-Like Peptide (MLP; Part A) (Primary), Mean, ng/mL: Part A: 0.38 mg/kg 4430 +/- 1175; Part A: 1.0 mg/kg 15500 +/- 2811; Part A: 2.0 mg/kg 32400 +/- 7005; Part A: 3.0 mg/kg 50650 +/- 7461; Part A: 4.0 mg/kg 75625 +/- 8152; Part A: 5.0 mg/kg 93275 +/- 6133; Part A: 6.0 mg/kg 115750 +/- 11871; Part A: 7.0 mg/kg 130250 +/- 14127; Part A: 8.0 mg/kg 167000 +/- 7810
• Pharmacokinetics of ARC-AAT: Time to Maximum Observed Concentration (Tmax) for the Analytes AD00370 and ARC-MLP (Part A) (Primary), Median, hour: Part A: 0.38 mg/kg 0.083 (0.083 to 0.25); Part A: 1.0 mg/kg 0.083 (0.083 to 0.083); Part A: 2.0 mg/kg 0.083 (0.083 to 0.083); Part A: 3.0 mg/kg 0.083 (0.083 to 0.50); Part A: 4.0 mg/kg 0.083 (0.083 to 0.083); Part A: 5.0 mg/kg 0.083 (0.083 to 0.50); Part A: 6.0 mg/kg 0.083 (0.083 to 0.50); Part A: 7.0 mg/kg 0.083 (0.083 to 0.50); Part A: 8.0 mg/kg 0.50 (0.083 to 0.50)
• Pharmacokinetics of ARC-AAT: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Time 24 Hours (AUC0-24) for the Analytes AD00370 and ARC-MLP (Part A) (Primary), Mean, hr*ng/mL: Part A: 0.38 mg/kg 26905 +/- 10793; Part A: 1.0 mg/kg 85138 +/- 12234; Part A: 2.0 mg/kg 162198 +/- 56129; Part A: 3.0 mg/kg 282710 +/- 61810; Part A: 4.0 mg/kg 438532 +/- 38111; Part A: 5.0 mg/kg 541628 +/- 49787; Part A: 6.0 mg/kg 708648 +/- 212442; Part A: 7.0 mg/kg 763392 +/- 96095; Part A: 8.0 mg/kg 908117 +/- 144892
• Pharmacokinetics of ARC-AAT: Area Under the Plasma Concentration Versus Time Curve From From Zero to Infinity (AUCinf) for the Analytes AD00370 and ARC-MLP (Part A) (Primary), Mean, hr*ng/mL: Part A: 0.38 mg/kg 27388 +/- 11183; Part A: 1.0 mg/kg 85906 +/- 12529; Part A: 2.0 mg/kg 164856 +/- 58070; Part A: 3.0 mg/kg 285487 +/- 62310; Part A: 4.0 mg/kg 441239 +/- 39032; Part A: 5.0 mg/kg 547045 +/- 52126; Part A: 6.0 mg/kg 719843 +/- 226599; Part A: 7.0 mg/kg 771924 +/- 100469; Part A: 8.0 mg/kg 916343 +/- 147924
• Pharmacokinetics of ARC-AAT: Terminal Elimination Rate Constant Obtained From the Slope of the Line (Kel) for the Analytes AD00370 and ARC-MLP (Part A) (Primary), Mean, 1/hour: Part A: 0.38 mg/kg 0.186 +/- 0.050; Part A: 1.0 mg/kg 0.177 +/- 0.004; Part A: 2.0 mg/kg 0.170 +/- 0.013; Part A: 3.0 mg/kg 0.174 +/- 0.004; Part A: 4.0 mg/kg 0.185 +/- 0.011; Part A: 5.0 mg/kg 0.183 +/- 0.006; Part A: 6.0 mg/kg 0.185 +/- 0.023; Part A: 7.0 mg/kg 0.178 +/- 0.010; Part A: 8.0 mg/kg 0.181 +/- 0.009
• Pharmacokinetics of ARC-AAT: Half-Life (t1/2) for the Analytes AD00370 and ARC-MLP (Part A) (Primary), Mean, hours: Part A: 0.38 mg/kg 3.90 +/- 0.84; Part A: 1.0 mg/kg 3.91 +/- 0.09; Part A: 2.0 mg/kg 4.09 +/- 0.31; Part A: 3.0 mg/kg 3.99 +/- 0.09; Part A: 4.0 mg/kg 3.75 +/- 0.22; Part A: 5.0 mg/kg 3.78 +/- 0.12; Part A: 6.0 mg/kg 3.80 +/- 0.53; Part A: 7.0 mg/kg 3.90 +/- 0.23; Part A: 8.0 mg/kg 3.83 +/- 0.19
• Percentage Reduction From Baseline of AAT Up to Day 29 (Primary), Mean, percentage reduction: Part A: 0.38 mg/kg -4.70 +/- 8.45; Part A: 1.0 mg/kg -7.00 +/- 3.19; Part A: 2.0 mg/kg -1.94 +/- 4.49; Part A: 3.0 mg/kg 13.76 +/- 4.74; Part A: 4.0 mg/kg 20.76 +/- 5.86; Part A: 5.0 mg/kg 21.65 +/- 5.28; Part A: 6.0 mg/kg 22.20 +/- 8.80; Part A: 7.0 mg/kg 20.35 +/- 11.83; Part A: 8.0 mg/kg 30.07 +/- 6.37; Part A: Placebo -4.65 +/- 11.13; Part B: 2.0 mg/kg 11.5 +/- 11.5; Part B: 4.0 mg/kg 43.8 +/- 5.6; Part B: Placebo -13.0 +/- 31.9
• Number of Participants With AAT Reduction > 30% From Baseline (First Occurrence) (Secondary), Number, participants: Part A: 0.38 mg/kg 0; Part A: 1.0 mg/kg 2; Part A: 2.0 mg/kg 2; Part A: 3.0 mg/kg 3; Part A: 4.0 mg/kg 4; Part A: 5.0 mg/kg 4; Part A: 6.0 mg/kg 4; Part A: 7.0 mg/kg 4; Part A: 8.0 mg/kg 3; Part A: Placebo 0; Part B: 2.0 mg/kg 2; Part B: 4.0 mg/kg 3; Part B: Placebo 1
• Maximum Percentage Reduction in Mean AAT (Nadir of Mean AAT) (Secondary), Number, percentage reduction: Part A: 0.38 mg/kg 5.0; Part A: 1.0 mg/kg 25.9; Part A: 2.0 mg/kg 26.7; Part A: 3.0 mg/kg 35.5; Part A: 4.0 mg/kg 61.5; Part A: 5.0 mg/kg 77.2; Part A: 6.0 mg/kg 83.1; Part A: 7.0 mg/kg 81.1; Part A: 8.0 mg/kg 87.9; Part A: Placebo 0.78; Part B: 2.0 mg/kg 43.1; Part B: 4.0 mg/kg 77.7; Part B: Placebo 7.2
• Number of Participants With a Return From Nadir AAT Blood Levels to Above Normal or Within 15% of Baseline in > 100 Days (Secondary), Number, participants: Part A: 0.38 mg/kg 4; Part A: 1.0 mg/kg 4; Part A: 2.0 mg/kg 4; Part A: 3.0 mg/kg 4; Part A: 4.0 mg/kg 4; Part A: 5.0 mg/kg 4; Part A: 6.0 mg/kg 4; Part A: 7.0 mg/kg 4; Part A: 8.0 mg/kg 4; Part A: Placebo 18; Part B: 2.0 mg/kg 4; Part B: 4.0 mg/kg 3; Part B: Placebo 4
• Mean Percentage Change in Circulating Blood Levels of Cytokines 2 Hours Post-Dose (Secondary), Mean, percentage change: Part A: 0.38 mg/kg 0 +/- 0; Part A: 1.0 mg/kg 0 +/- 0; Part A: 2.0 mg/kg 0 +/- 0; Part A: 3.0 mg/kg 0 +/- 0; Part A: 4.0 mg/kg 0 +/- 0; Part A: 5.0 mg/kg 0 +/- 0; Part A: 6.0 mg/kg 0 +/- 0; Part A: 7.0 mg/kg -9 +/- 17; Part A: 8.0 mg/kg 9 +/- 18; Part A: Placebo 0 +/- 0; Part B: 2.0 mg/kg -2 +/- 10; Part B: 4.0 mg/kg 114 +/- NA; Part B: Placebo 0 +/- 0
• Mean Percentage Change in Circulating Blood Levels of Complement Factors 2 Hours Post-Dose (Secondary), Mean, percentage change: Part A: 0.38 mg/kg 18 +/- 16; Part A: 1.0 mg/kg 56 +/- 25; Part A: 2.0 mg/kg 76 +/- 37; Part A: 3.0 mg/kg 133 +/- 29; Part A: 4.0 mg/kg 181 +/- 185; Part A: 5.0 mg/kg 137 +/- 85; Part A: 6.0 mg/kg 70 +/- 63; Part A: 7.0 mg/kg 147 +/- 73; Part A: 8.0 mg/kg 309 +/- 174; Part A: Placebo -7 +/- 9; Part B: 2.0 mg/kg 56 +/- 61; Part B: 4.0 mg/kg 59 +/- NA; Part B: Placebo -14 +/- 7

Adverse events

Time frame: Day -1 through Day 29 ± 1 day

Serious adverse events by term

Other adverse events by term

• Results publication: Turner AM, Stolk J, Bals R, Lickliter JD, Hamilton J, Christianson DR, Given BD, Burdon JG, Loomba R, Stoller JK, Teckman JH. Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients. J Hepatol. 2018 Aug;69(2):378-384. doi: 10.1016/j.jhep.2018.03.012. Epub 2018 Mar 21. PMID 29572094

NIH grants: 2015