A Phase 1 Study to Assess the Safety of NLY01 in Healthy Subjects

This is a Phase 1, first-in-human, double-blind, randomized, placebo-controlled, single and multiple-dose study to assess the safety, tolerability, and PK of NLY01, a PEGylated form of the anti-diabetic peptide exenatide, when administered by SC injection in healthy subjects.

In Part A of the study, 5 ascending-dose cohorts will be sequentially enrolled with an evaluation of safety and tolerability prior to each dose-escalation. Subjects in each cohort will be randomized to receive NLY01 or placebo. Each dose escalation and selection of doses for Part B will be conducted with oversight by an independently-chaired Safety Review Committee.

In Part B, subjects will receive once-weekly subcutaneous doses of NLY01 or placebo for 4 weeks. Three ascending-dose cohorts will be sequentially-enrolled with a safety review prior to each dose-escalation. Subjects in all Part B cohorts will receive fixed doses of NLY01 (or placebo) once-weekly for 4 weeks.

Inclusion criteria

• Men or women, 18 to 65 years of age, inclusive.
• BMI ≥ 18.5 and ≤ 32.0 kg/m2 at screening and check-in. BMI = weight (kg)/(height [m])2.
• Women of child-bearing potential must agree to use a medically acceptable method of contraception from screening through 30 days after the final dose of study drug.
• Non-childbearing potential.
• Men who are sexually active and whose partners are women of child-bearing potential must agree to use condoms from screening through 90 days after administration of study drug, and their partners must be willing to use a medically acceptable method of contraception (a barrier method, intrauterine device, or hormonal contraception) from screening through 90 days after administration of the last dose of study drug.
• Men must agree to not donate sperm from screening through 90 days after study drug administration.
• Subjects must be able to communicate effectively with the study personnel.
• Subjects must be healthy and without clinically significant abnormalities as assessed by review of medical and surgical history, physical examination, vital signs measurement, ECG, and laboratory evaluations conducted at screening and on Day -1 Check-in. A single repeat measurement/test may be performed to confirm vital signs, ECG, and clinical laboratory tests abnormalities (ie, to confirm that a subject is eligible).
• Subjects must be nonsmokers, defined as having abstained from tobacco- or nicotine containing products (eg, cigarettes, chewing tobacco, snuff, nicotine patches, and electronic cigarettes) in the 6 months prior to screening.
• Subjects must be informed of the nature and risks of the study and give written informed consent prior to screening.

Exclusion criteria

• Positive pregnancy test or is lactating/breastfeeding.
• History or presence of conditions which, in the judgment of the investigator, are known to interfere with the distribution, metabolism, or excretion of drugs.
• History or presence of conditions that may place the subject at increased risk as determined by the investigator.
• History of surgery or major trauma within 12 weeks of screening, or surgery planned during the study.
• History of alcohol abuse, illicit drug use, significant mental illness, physical dependence to any opioid, or any history of drug abuse or addiction within 12 months of screening.
• Use of prescription, OTC drugs (including herbal preparations) within 7 days or 5 half lives (if known), whichever is longer, prior to administration of the first dose of study drug.
• Has received a vaccination within 14 days prior to administration of the first dose of study drug.
• Has taken other investigational drugs or participated in any clinical study within 60 days or 5 half-lives (if known) of the investigational drug's PK, PD, or biological activity (if known), whichever is longer, prior to administration of the first dose of study drug in this study or is currently participating in another clinical study.
• Prior exposure to exenatide (Byetta® or Bydureon®).
• Significant blood loss (> 450 mL) or has donated 1 or more units of blood or plasma within 6 weeks prior to study randomization.
• History of hypoglycemia.
• History of gastroparesis.
• History of pancreatitis.
• Positive urine results for drugs of abuse, alcohol, or cotinine screen.
• Positive screen for HIV-1 and HIV-2 antibodies, HBsAg, or HCV antibody.
• Clinically significant cardiac changes demonstrated by ECG at screening or Day-1 including:

• QTcF interval > 450 msec
• PR interval ≤ 110 msec or > 240 msec
• Evidence of second- or third-degree atrioventricular block
• Pathological Q-waves (defined as Q-wave > 40 msec or depth greater than 0.5 mV)
• Evidence of ventricular pre-excitation
• Evidence of complete left BBB, incomplete left BBB, complete right BBB
• Intraventricular conduction delay with QRS duration > 120 msec
• Bradycardia (defined as sinus rate < 50 bpm) or tachycardia (defined as sinus rate > 100 bpm)
• Has any of the following abnormal vital signs at screening or Day-1:

• Pulse < 40 or > 100 bpm
• Respiratory rate < 8 or > 20 breaths per minute
• Systolic blood pressure < 95 or > 145 mmHg
• Diastolic blood pressure < 45 or > 90 mmHg
• Serum potassium, chloride, calcium, or sodium outside the normal reference range at screening
• Hepatic transaminases (ALT or AST) > 100 IU/mL at screening.
• Any hematology, chemistry, or urinalysis test results that are clinically significant.
• Any other condition or prior therapy that, in the investigator's opinion, would make the subject unsuitable for the study, or unable or unwilling to comply with the study procedures.
• Unwilling or unlikely to comply with the requirements of the study.