a study of arc-aat in healthy volunteer subjects and patients with alpha-1 antitrypsin deficiency (aatd)

Conditions: Alpha-1 Antitrypsin Deficiency

Summary: the purpose of the study is to determine the safety and tolerability of escalating doses of arc-aat and to evaluate the pharmacokinetics of arc-aat and the effect of arc-aat on circulating levels of alpha-1 antitrypsin (aat). the study will consist of two parts, part a (conducted in healthy volunteers) and part b (conducted in aatd patients) at up to 9 escalating dose levels with 6 participants per dose level.

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.

Eligibility criteria:
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

Keywords: alpha-1 antitrypsin aatd