Evaluate the Immunogenicity of a Novel Glucagon Formulation

Condition(s) targeted: Drug-specific Antibodies; Hypoglycemia; Diabetes Mellitus

Intervention: Glucagon IN (Drug); Glucagon IM (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Locemia Solutions ULC

Official(s) and/or principal investigator(s):
Eric Sicard, MD, Principal Investigator, Affiliation: Algorithme Pharma Inc

In recent past years, regulatory agencies such as FDA and EMA have outlined and recommended adoption of a risk-based approach to evaluating and mitigating immune responses to therapeutic proteins that may adversely affect their safety and efficacy. In their recommendations, both transient and persistent antibody responses should be combined to determine the overall immunogenicity of a product in a given condition. In particular, persistent antibodies are of high importance, since patients with persistent antibodies are more likely to experience clinical sequelae in terms of safety and efficacy, while a transient antibody response can resolve without further consequence. The present study will provide information on immunogenicity of AMG504-1 with regards to the potential development of high antibody titers or neutralizing antibody activity which may lead to loss of efficacy or an increased risk of an adverse reaction.

Official title: A Single Center, Randomized, Parallel Safety Study To Evaluate The Immunogenicity Of A Novel Glucagon Formulation Compared To Commercially Available Glucagon Administered By Intramuscular Injection In Adults With Type 1 OR Type 2 Diabetes

Study design: Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label

Primary outcome: Immunogenicity data (titers)

Secondary outcome: Safety and tolerability

Detailed description: AMG105 is a single center, randomized, single dose, laboratory-blinded, parallel design study. The main objective of this study is to evaluate the immunogenicity of repeated single doses of glucagon following intranasal (IN) and intramuscular (IM) administration in adults with Type 1 or Type 2 diabetes (T1D or T2D). The secondary objective is to evaluate the safety and tolerability of glucagon following IN and IM administration in adults with T1D or T2D. A total of seventy-five (75) adult patients with T1D or T2D will be included in the study. Male and female patients of at least 18 years of age but not older than 70 years with a history of type 1 diabetes or type 2 diabetes of at least 2 years duration, and with a body mass index (BMI) greater than or equal to 18. 5 and below or equal to 35 kg/m2 will be selected according to the inclusion and exclusion criteria. They will be in general good health, without late severe complications, according to medical history, physical examination (including vital signs), nasal examination, bilateral anterior rhinoscopy and laboratory tests (biochemistry, hematology, urinalysis) including negative screening of ethanol and drugs of abuse in urine. A 12-lead ECG will be performed. For female patients, a HCG beta serum pregnancy test must be negative. A single dose of glucagon will be administered in the morning after a 10-hour overnight fast, either by intranasal or intramuscular route, on 3 occasions. The random allocation of each treatment to each subject will be generated using a 2: 1 stratification. Safety and tolerability will be evaluated through the assessment of adverse events, clinical and laboratory examinations. Descriptive statistics comprising the sample size, mean, median, SD and 95% confidence intervals (CI) of the mean will be used to describe the titer of anti-glucagon antibodies in each treatment group by period. In addition, the number, proportion and associated 95% CI of patients in each treatment group with anti-glucagon antibodies above the limit of detection will be described.

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Availability for the entire study period 2. Motivated volunteer and absence of intellectual problems likely to limit the validity of consent to participate in the study or the compliance with protocol requirements; ability to cooperate adequately; ability to understand and observe the instructions of the physician or designee 3. Male or female patient with a history of Type 1 or Type 2 diabetes of at least 2 years duration 4. A female volunteer must meet one of the following criteria: 1. Participant is of childbearing potential and agrees to use one of the accepted contraceptive regimens throughout the entire duration of the study (from the screening visit until study completion). Additionally, if the participant is using systemic contraceptives, she must use an additional form of acceptable contraception. An acceptable method of contraception includes one of the following:

- Abstinence from heterosexual intercourse

- Systemic contraceptives (birth control pills, injectable/implant

/insertable hormonal birth control products, transdermal patch)

- Intrauterine device (with and without hormones)

- Condom with spermicide

or 2. Participant is of non-childbearing potential, defined as surgically sterile (i. e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or in a menopausal state (at least 1 year without menses) 5. Volunteer aged of at least 18 years but not older than 70 years 6. Volunteer with a BMI greater than or equal to 18. 50 and below 35. 00 kg/m2 7. Light-, non- or ex-smokers. A light smoker is defined as someone smoking 10 cigarettes or less per day for at least 3 months before day 1 of this study. An ex- smoker is defined as someone who completely stopped smoking for at least 6 months before day 1 of this study 8. In good general health with no conditions that could influence the outcome of the trial, and in the judgment of the Investigator is a good candidate for the study based on review of available medical history, physical examination and clinical laboratory evaluations 9. Willingness to adhere to the protocol requirements as evidenced by the informed consent form (ICF) duly read, signed and dated by the volunteer The informed consent form must be signed by all volunteers, prior to their participation in the study. Exclusion Criteria: 1. Females who are pregnant, actively attempting to get pregnant, or are lactating 2. History of significant hypersensitivity to glucagon or any related products as well as severe hypersensitivity reactions (such as angioedema) to any drugs 3. Presence of significant gastrointestinal, liver or kidney disease, or any other conditions which in the judgment of the Investigator could interfere with the absorption, distribution, metabolism or excretion of drugs, or could potentiate or predispose to undesired effects 4. Suicidal tendency, history of or disposition to seizures, state of confusion, clinically relevant psychiatric diseases 5. Known presence of rare hereditary problems of galactose and /or lactose intolerance 6. Known presence or history of pheochromocytoma (i. e. adrenal gland tumor) or insulinoma (i. e. insulin secreting pancreas tumor) 7. Presence of clinically significant findings on nasal examination or bilateral anterior rhinoscopy, such as structural abnormalities, nasal polyps, marked septal deviation, nasal tumors 8. Nasal surgery in the previous 28 days before Day 1 of this study 9. Use of a systemic beta-blocker drug, indomethacin, warfarin or anticholinergic drugs in the previous 28 days before Day 1 of this study 10. Use of an immunomodulator medication (including steroids, glucocorticoids, tacrolimus, etc.) in the 28 days before day 1 of this study 11. Any other concomitant maintenance therapy that would influence the outcome of the trial or compromise the safety of the patient, at the discretion of the Investigator and the Sponsor, in the previous 28 days before day 1 of this study 12. Significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) 13. Any clinically significant illness in the previous 28 days before day 1 of this study 14. Any history of tuberculosis and/or prophylaxis for tuberculosis 15. Positive urine screening of alcohol and/or drugs of abuse 16. Females who are pregnant according to a positive pregnancy test 17. Concurrent participation or intention of participating in another clinical trial during this study 18. Volunteers who took an Investigational Product (in another clinical trial) or donated 50 mL or more of blood in the previous 28 days before day 1 of this study 19. Donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the previous 56 days before day 1 of this study No patients will be allowed to enroll in this study more than once (i. e. if the study is conducted with more than 1 group).

Algorithme Pharma Inc., Laval, Quebec H7V 4B3, Canada

Starting date: September 2013
Last updated: July 7, 2015