NAVX-010-Phase I Tolerability and Pharmacokinetic Study in Healthy Male Subjects

This was a double-blind, placebo-controlled, randomized, single ascending dose, sequential group study. Each subject participated in only 1 treatment period.

The primary objective was to determine the safety of single intramuscular (IM) injections of NAVX 010 in healthy subjects. The secondary objective was to determine the single dose pharmacokinetics (PK) of Gonyautoxin 2 (GTX 2) and Gonyautoxin 3 (GTX 3) following IM administration of NAVX 010 in healthy subjects.

Thirty subjects were studied in 5 groups (Groups A to E); each group consisted of 6 subjects, of which 4 subjects received the Investigational Medicinal Product and 2 subjects received placebo. All subjects completed the study and data for all subjects were included in the safety analyses. A total of 20 subjects received NAVX-010 and were included in the PK population and subsequent PK analysis.

This was a double-blind, placebo-controlled, randomized, single ascending dose, sequential group study. Each subject participated in only 1 treatment period.

The primary objective was to determine the safety of single intramuscular (IM) injections of NAVX-010 in healthy subjects. The secondary objective was to determine the single dose pharmacokinetics (PK) of Gonyautoxin 2 (GTX 2) and Gonyautoxin 3 (GTX 3) following IM administration of NAVX-010 in healthy subjects.

Thirty subjects were studied in 5 groups (Groups A to E); each group consisted of 6 subjects, of which 4 subjects received the Investigational Medicinal Product (IMP; NAVX-010) and 2 subjects received placebo. All subjects completed the study and data for all subjects were included in the safety analyses. A total of 20 subjects received NAVX-010 and were included in the PK population and subsequent PK analysis.

This study comprised healthy male subjects of any ethnic origin, aged between 18 and 45 years, inclusive, and with a body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive.

Dose levels of NAVX-010 were 2, 8, 25, 50, and 75 mcg. Doses were administered as IM injections into the deltoid muscle in the fasted state. The IMP was supplied in glass vials containing 1.2 mL solution at a total GTX 2 and GTX 3 concentration of 42 mcg/mL (at a relative epimer ratio of 62% GTX 2:38% GTX 3).

Placebo was of identical appearance to the IMP, and was administered into the deltoid muscle in the fasted state.

Single IM injections were administered in each group. Blood and urine samples were collected for the analysis of plasma and urinary concentrations of GTX 2 and GTX 3, and the following PK parameters for GTX 2 and GTX 3 were calculated: area under the concentration-time curve (AUC) from time 0 up to the time of last quantifiable plasma concentration (AUC0 t), AUC from time 0 to 24 hours postdose (AUC0-24), AUC from time 0 extrapolated to infinity (AUC0 ∞), percentage of AUC that is due to extrapolation from the time of last quantifiable concentration to infinity (%AUCextrap), maximum observed plasma concentration (Cmax), time of the maximum observed plasma concentration (tmax), time of last quantifiable plasma concentration (tlast), time before the start of absorption (tlag), apparent plasma terminal elimination half life (t½), apparent total plasma clearance (CL/F), apparent volume of distribution during the terminal elimination phase (Vz/F), amount of drug excreted in urine (Ae), percentage of dose excreted in urine (Fe), and renal clearance (CLR).

Safety evaluations included adverse events (AEs), vital signs, 12 lead electrocardiogram (ECG), telemetry, clinical laboratory evaluations, physical examination, and clinical study questionnaires.

Eligibility Criteria:
Inclusion Criteria:

* males
* between 18 and 45 years of age
* body mass index (BMI) between 18.0 and 32.0 kg/m2 inclusive
* body weight between 50 kg and 100 kg inclusive
* Subjects must be in good health, as determined by:
* medical history
* physical examination (at check-in)
* vital sign assessment
* 12-lead ECG
* clinical laboratory evaluations
* Subjects must be able to understand and respond to the clinical study questionnaire
* Subjects will have given their written informed consent to participate in the study and to abide by the study restrictions

Exclusion Criteria:

* Male subjects who are not willing, or whose partners are not willing, to use appropriate contraception (such as a condom with spermicidal oam/gel/film/cream/suppository), or to refrain from donating sperm from the time of dosing until 3 months after study drug administration.
* Male subjects whose partners are of child-bearing potential must also agree to use an additional highly effective method of contraception.
* Subjects who have donated;
* blood or platelets in the 3 months prior to screening
* plasma in the 7 days prior to screening
* Subjects who have a significant history of alcoholism or drug/chemical abuse as determined by the Investigator or consume alcohol within 48 hours prior to the screening visit and prior to check-in.
* Subjects who have smoked more than 10 cigarettes per day or the equivalent in tobacco use (e.g. chewing tobacco, eCigarettes and smoking cessation products \[nicotine patch or gum\]) during the 3 months prior to screening.
* Subjects who have used the following within 7 days prior to study drug administration, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety:
* any over-the-counter systemic or topical medication
* herbal remedies
* vitamin supplements
* mineral supplements
* Subjects who have received any medications, including St John's Wort, known to chronically alter drug absorption or elimination processes within 30 days prior to study drug administration unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety.
* Subjects who have received:
* any prescribed systemic or topical medication within 15 days prior to study drug administration unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety.
* slow release medicinal formulations considered to still be active within 15 days prior to study drug administration, unless in the opinion of the Investigator, the medication will not interfere with the study procedures or compromise safety.
* coumarins (e.g. warfarin) at any time in the subject's lifetime.
* Subjects who have an abnormality in heart rate, blood pressure, temperature, oxygen saturation or respiration rate that, in the opinion of the Investigator, increases the risk of participating in the study, at screening and prior to study drug administration.
* Specific exclusion criteria at screening and/or prior to dosing are heart rate \<40 bpm or \>110 bpm, systolic blood pressure \<90 mmHg or \>150 mmHg, diastolic blood pressure \<40 mmHg or \>90 mmHg, oxygen saturation \<94%, confirmed by a repeat assessment.
* Subjects with a positive urine drug or alcohol screen at screening or first admission.
* Subjects who have an abnormality in the 12-lead ECG that, in the opinion of the Investigator, increases the risk of participating in the study, at screening and prior to study drug administration.
* Specific exclusion criterion at screening and/or prior to dosing is QTcF value \>450 ms, confirmed by a repeat assessment.
* Subjects who are still participating in a clinical study (e.g. attending follow-up visits) or who have been administered an investigational drug (new chemical entity) in the 30 days prior to study drug administration.
* Subjects with a significant history of drug allergy as determined by the Investigator, including known or suspected allergy to any of the study drug components.
* Subjects with a known or suspected shellfish allergy or a positive skin prick test for shellfish allergy at screening or first admission.
* Subjects who have any clinically significant abnormal physical examination finding at check-in (Day -1 or Day -2). Specific exclusion criterion is any skin condition or finding that would limit a local injection site examination.
* Subjects who have any clinically significant allergic condition (excluding non-active hayfever) as determined by the Investigator.
* Subjects with, or with a history of, any clinically significant neurological, gastrointestinal, renal, hepatic, cardiovascular, psychiatric, respiratory, metabolic, endocrine, haematological or other major disorders as determined by the Investigator.
* Subjects who have had a clinically significant illness within 4 weeks of the start of dose administration as determined by the Investigator.
* Subjects who have any clinically significant abnormal laboratory safety findings, in the opinion of the Investigator (one repeat assessment is acceptable), at screening and prior to study drug administration.
* Specific exclusion criteria at screening and/or prior to dosing are fasting serum glucose \<60 mg/dL or \>115 mg/dL, serum phosphorous \>1.5 х upper limit of normal (ULN), serum blood urea nitrogen \>1.5 х ULN, serum alanine aminotransferase (ALT) \>1.5 х ULN, serum aspartate aminotransferase (AST) \>1.5 х ULN, serum total bilirubin \>1.5 х ULN, serum creatinine \>1.5 х ULN, hemoglobin \<12 g/100 mL.
* Subjects who:
* are known to have serum hepatitis
* are carriers of the hepatitis B surface antigen (HBsAg)
* are carriers of the hepatitis C antibody
* have a positive result to the test for human immunodeficiency virus (HIV) antibodies.
* Subjects who have previously received a dose in this study.
* Subjects who, in the opinion of the Investigator, should not participate in the study.
* Subjects with a history of complications with anesthesia, such as malignant hyperthermia.