Summary Basis of Decision for Anthim
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Anthim is located below.
Recent Activity for Anthim
The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.
The following table describes post-authorization activity for Anthim, a product which contains the medicinal ingredient obiltoxaximab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).
For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.
Updated: 2024-06-28
Drug Identification Number (DIN):
DIN 02502895 – 100 mg/mL obiltoxaximab, solution, intravenous administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
NC # 284517 |
2024-02-29 |
Cancellation Letter Received 2024-04-12 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance and drug product release or shelf-life specifications. The sponsor cancelled the submission before Health Canada completed the review. |
|
NC # 270649 |
2022-12-14 |
Issued NOL 2023-03-10 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug substance and drug product (release and stability), and a change in the drug substance and drug product release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
Drug product (DIN 02502895) market notification |
Not applicable |
Date of first sale: 2022-09-13 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
Extraordinary Use NDS # 230825 |
2019-08-16 |
Issued NOC 2020-07-30 |
NOC issued for Extraordinary Use New Drug Submission. |
Summary Basis of Decision (SBD) for Anthim
Date SBD issued: 2021-01-28
The following information relates to the New Drug Submission for Anthim.
Obiltoxaximab
Drug Identification Number (DIN):
- DIN 02502895 - 100 mg/mL obiltoxaximab, solution, intravenous administration
Elusys Therapeutics, Inc.
New Drug Submission Control Number: 230825
On July 30, 2020, Health Canada issued a Notice of Compliance to Elusys Therapeutics, Inc. for the drug product Anthim.
Health Canada recognizes that there are extraordinary circumstances in which sponsors cannot reasonably provide substantial evidence demonstrating the efficacy and safety of a therapeutic product in humans as there are logistical or ethical challenges in conducting the appropriate human clinical trials. Therefore, the Extraordinary Use New Drugs regulatory pathway was used for authorization of Anthim based on quality, non-clinical and limited clinical information (see Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs]).
Based on Health Canada's review, the benefit‑risk profile of Anthim is favourable in adult and pediatric patients for the treatment of inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs, and for post‑exposure prophylaxis of inhalational anthrax due to B. anthracis when alternative therapies are not available or not appropriate.
The authorized indications are accompanied by important caveat statements and limitations of use. The effectiveness of Anthim is based solely on efficacy studies in animal models of inhalational anthrax, as it cannot be evaluated in humans for ethical reasons. Anthim should only be used for prophylaxis when its benefit for prevention of inhalational anthrax outweighs the risk of hypersensitivity and anaphylaxis. Anthim binds to the protective antigen component of B. anthracis toxin; it does not have direct antibacterial activity. Anthim is not expected to cross the blood-brain barrier and does not prevent or treat meningitis. Anthim should be used in combination with appropriate antibacterial drugs.
1 What was approved?
Anthim, a monoclonal antibody against Bacillus anthracis, was authorized for use in adult and pediatric patients for the treatment of inhalational anthrax due to B. anthracis in combination with appropriate antibacterial drugs, and for post‑exposure prophylaxis of inhalational anthrax due to B. anthracis when alternative therapies are not available or not appropriate.
The authorized indications are accompanied by important caveat statements and limitations of use. The effectiveness of Anthim is based solely on efficacy studies in animal models of inhalational anthrax, as it cannot be evaluated in humans for ethical reasons. Anthim should only be used for prophylaxis when its benefit for prevention of inhalational anthrax outweighs the risk of hypersensitivity and anaphylaxis. Anthim binds to the protective antigen component of the B. anthracis toxin; it does not have direct antibacterial activity. Anthim is not expected to cross the blood‑brain barrier and does not prevent or treat meningitis. Anthim should be used in combination with appropriate antibacterial drugs.
The safety and pharmacokinetics of Anthim have not been studied in the pediatric population (<18 years of age). A population pharmacokinetic approach was used to derive intravenous infusion dosing regimens, which are predicted to provide pediatric patients with exposure comparable to the observed exposure in adults.
Clinical studies of Anthim did not include sufficient numbers of geriatric subjects (≥65 years of age) to determine whether they respond differently from younger subjects. No dose modification is recommended for this patient population.
Anthim is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non‑medicinal ingredient, or component of the container.
Anthim was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Anthim (100 mg/mL obiltoxaximab) is presented as a solution. In addition to the medicinal ingredient, the solution contains hydrochloric acid, L‑histidine, polysorbate 80, sodium hydroxide, sorbitol and water for injection.
For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Anthim Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Anthim approved?
Health Canada considers that the benefit‑risk profile of Anthim is favourable for use in adult and pediatric patients for the treatment of inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs, and for post‑exposure prophylaxis of inhalational anthrax due to B. anthracis when alternative therapies are not available or not appropriate.
The authorized indications are accompanied by important caveat statements and limitations of use. The effectiveness of Anthim is based solely on efficacy studies in animal models of inhalational anthrax, as it cannot be evaluated in humans for ethical reasons. Anthim should only be used for prophylaxis when its benefit for prevention of inhalational anthrax outweighs the risk of hypersensitivity and anaphylaxis. Anthim binds to the protective antigen component of the B. anthracis toxin; it does not have direct antibacterial activity. Anthim is not expected to cross the blood‑brain barrier and does not prevent or treat meningitis. Anthim should be used in combination with appropriate antibacterial drugs.
Anthrax is a serious and life‑threatening disease caused by B. anthracis, a Gram‑positive, rod‑shaped bacterium that forms highly resistant spores under stressful environmental conditions. Inhalational anthrax, resulting from the inhalation of aerosolized B. anthracis spores, is the most serious form of the disease and has been associated with fatality rates as high as 90%. It is recognized that Anthrax can be used as a biological weapon.
Available treatments for anthrax include antibiotics and an antitoxin. Antibiotics are only effective against the vegetative state of B. anthracis, and not against spores. The antitoxin is a passive immunizing agent which neutralizes anthrax toxin. A preventative vaccine is also available.
Obiltoxaximab, the medicinal ingredient in Anthim, is a chimeric (human‑murine) immunoglobulin G1κ monoclonal antibody. It binds the protective antigen (PA) of the B. anthracis toxin, inhibiting the PA from binding to its cellular receptors, thereby preventing the anthrax lethal factor and the edema factor (the components responsible for the pathogenic effects of the anthrax toxin) from entering into the cell.
For ethical and logistical reasons, it is not possible to conduct well‑controlled clinical studies for treatments for inhalational anthrax. Therefore, Health Canada reviewed and authorized the sale of Anthim through the Extraordinary Use New Drugs (EUNDs) pathway, which was developed to allow a mechanism for the authorization of these drugs based on non‑clinical and limited clinical information. The efficacy of Anthim was evaluated in New Zealand White (NZW) rabbits and cynomolgus monkeys, two well‑characterized animal models of inhalational anthrax. Safety was evaluated in clinical studies in healthy human volunteers, as well as in non‑clinical studies.
Animal efficacy studies of Anthim were conducted in NZW rabbits and cynomolgus monkeys, and included trigger‑to‑treat studies, post‑exposure prophylaxis studies, pre‑exposure prophylaxis studies, and combination studies. The main primary endpoint was the survival rate at Day 28 post‑exposure.
Trigger‑to‑treat studies evaluated the treatment with Anthim after infection had been established in animals, as evidenced by the presence of protective antigen in the circulation and the development of fever. The treatment was delayed to allow disease to be established. Higher survival rates (31% to 93%) were observed in groups that received a single 16 mg/kg dose of Anthim, relative to survival rates observed in placebo groups (0% to 6%). Additionally, the combination of Anthim and antibiotics was also associated with higher survival outcomes in animal models of inhalational anthrax than treatment with antibiotic therapy alone.
Non‑clinical pre‑ and post‑exposure prophylaxis studies were conducted. However, an indication for pre‑exposure prophylaxis is not acceptable, as the duration of the protection provided by Anthim is unclear.
Overall, the animal studies demonstrated the efficacy of Anthim at a dose level of 16 mg/kg, administered intravenously as monotherapy or in combination with antibiotics for the treatment of inhalational anthrax in monkeys and rabbits.
In non‑clinical studies, central nervous system lesions were observed in anthrax‑infected non‑surviving animals in groups that received Anthim (≥4 mg/kg) as well as in the control groups. No treatment‑related brain lesions were detected in anthrax‑infected surviving NZW rabbits at Day 28 after single doses up to 16 mg/kg, or in cynomolgus monkeys up to Day 56 after doses up to 32 mg/kg. Hemorrhage or hemorrhagic meningoencephalitis were observed in surviving animals treated with obiltoxaximab as well as surviving animals in the control group. These effects were therefore not considered related to treatment. No neurobehavioral effects related to obiltoxaximab were observed in surviving anthrax‑infected cynomolgus monkeys following treatment. The safety profile obtained from animal studies is considered acceptable.
The safety of Anthim was evaluated in 320 healthy adult subjects in three clinical trials with a dose level of 16 mg/kg. Pruritus, rash, cough, infusion site swelling, urticaria, and injection site pain were the most frequently reported adverse events considered at least possibly related to the administration of Anthim. The combination of Anthim and ciprofloxacin was well tolerated in the 20 subjects who received both drugs in Study AH110.
Hypersensitivity reactions and anaphylaxis were the main safety concerns. These risks were highlighted in a Serious Warnings and Precautions box in the Anthim Product Monograph, along with instructions for proper administration and monitoring. Pre‑medication with diphenhydramine, an antihistamine, is recommended prior to the administration of Anthim.
Follow‑up for healthy subjects in the clinical safety studies continued for up to 190 days post dosing. Long‑term safety data were not available at the time of authorization, and there are no post‑market data as Anthim is not commercially available in any countries.
There have been no studies of the safety or pharmacokinetics of Anthim in the pediatric population. A population pharmacokinetics approach was used to derive intravenous infusion dosing regimens that are predicted to provide pediatric patients with exposure comparable to the observed exposure in adults. Recommended doses for pediatric patients (<18 years of age) are based on body weight.
A Risk Management Plan (RMP) for Anthim was submitted by Elusys Therapeutics, Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Anthim Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Anthim was accepted.
Overall, the therapeutic benefit of Anthim, as inferred from the submitted animal efficacy studies, outweighs the known and expected risks of the product. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Anthim Product Monograph to address the identified safety concerns.
This Extraordinary Use New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. The sale of Anthim, as an authorized extraordinary use new drug, is restricted to authorized entities such as the federal, provincial, territorial and municipal government(s).
For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Anthim?
Submission Milestones: Anthim
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2019-05-06 |
| Submission filed: | 2019-08-15 |
| Screening | |
| Screening Acceptance Letter issued: | 2019-10-04 |
| Review | |
| Review of Risk Management Plan complete: | 2020-04-24 |
| Quality Evaluation complete: | 2020-07-24 |
| Clinical/Medical Evaluation complete: | 2020-07-24 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2020-07-28 |
| Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate: | 2020-07-30 |
The Canadian regulatory decision on the review of Anthim was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was consulted for relevant supplementary information.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
4 What follow-up measures will the company take?
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
Obiltoxaximab, the medicinal ingredient in Anthim, is a monoclonal antibody that binds the protective antigen (PA) of Bacillus anthracis. This inhibits the PA from binding to its cellular receptors, thereby preventing the anthrax lethal factor and the edema factor (the components responsible for the pathogenic effects of the anthrax toxin) from entering into the cell.
The pharmacokinetic profile of Anthim has been characterized in healthy adult human volunteers, and is linear over the dose range of 4‑16 mg/kg following intravenous administration of a single dose. The mean steady‑state volume of distribution was greater than plasma volume, suggesting some tissue distribution. Formal metabolism and excretion studies have not been conducted with Anthim. Monoclonal antibodies are typically catabolized by proteases, and the resulting small peptides and amino acids are either incorporated into the endogenous pool or excreted. Clearance values indicate that there is virtually no renal clearance of obiltoxaximab. The half‑life of Anthim in healthy adults was approximately 20 days following a single intravenous dose of 16 mg/kg. The maximum plasma concentration (Cmax), exposure over time as measured by the area under the concentration‑time curve (AUC), and half‑life of Anthim were similar when Anthim was administered alone or with ciprofloxacin (intravenously or orally).
The efficacy of Anthim has not been evaluated in humans. To provide evidence in support of the proposed 16 mg/kg single intravenous dose, exposure levels achieved in healthy adult human subjects were compared to those observed in animal models of inhalational anthrax. Population pharmacokinetic and survival analysis models were reviewed for this purpose, and included pharmacology and pharmacokinetic data from New Zealand White (NZW) rabbits and cynomolgus monkeys, as well as pharmacokinetic data in healthy humans. Collectively, the observed and simulated data indicated that a single 16 mg/kg intravenous dose yields similar exposures in humans (as measured by Cmax and by AUC from time zero to infinity, AUCinf) as exposures achieved in NZW rabbits and cynomolgus monkeys that received the fully effective dose.
Pharmacokinetic studies have not been conducted in pediatric subjects. The doses that would yield exposures in pediatric subjects comparable to those observed in adults were determined based on population pharmacokinetic simulations. Weight‑based dosing is recommended for pediatric patients, taking into account the risk of hypersensitivity to Anthim and meaningful survival observed in animals at doses as low as 8 mg/kg.
The pharmacodynamics of Anthim has not been studied in humans.
For further details, please refer to the Anthim Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Health Canada recognizes that there are circumstances in which sponsors cannot reasonably provide substantial evidence demonstrating the efficacy and safety of a therapeutic product in humans as there are logistical or ethical challenges in conducting the appropriate human clinical trials. The Extraordinary Use New Drugs (EUNDs) submission pathway was developed to allow a mechanism for authorization of these products based on non‑clinical and limited clinical information (see Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs]).
As it is not ethical or feasible to conduct controlled clinical trials in humans with inhalational anthrax, the efficacy of Anthim was evaluated in non‑clinical studies in New Zealand White rabbits and cynomolgus monkeys. Clinical safety studies of Anthim have only been conducted in healthy adult volunteers, and are described in the Clinical Safety section.
For more information, refer to the Anthim Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Anthim at a dose level of 16 mg/kg was evaluated in healthy adult volunteers (subjects), in three studies: AH104, AH109, and AH110.
Study AH104 was designed to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of a single dose of Anthim. A total of 280 subjects were enrolled, with 210 subjects randomized to receive a 16 mg/kg dose of Anthim as a 90‑minute intravenous infusion, and 70 subjects randomized to receive a placebo.
Study AH109 was a Phase I study designed to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of repeat administration of Anthim in healthy adult volunteers. Seventy subjects were randomized to receive Anthim in one of two sequences: 35 subjects in Sequence A (16 mg/kg Anthim on Day 1, 16 mg/kg Anthim on Day 14, and placebo on Day 120), and 35 subjects in Sequence B (16 mg/kg Anthim on Day 1, placebo on Day 14, and 16 mg/kg Anthim on Day 120).
Study AH110 was designed to evaluate the safety, tolerability, and pharmacokinetics of Anthim administered alone and administered with ciprofloxacin. Forty subjects were randomized, with 20 subjects receiving Anthim alone (16 mg/kg intravenous dose), and 20 subjects receiving Anthim (16 mg/kg intravenous dose) along with ciprofloxacin (400 mg intravenous dose on Day 1, followed by 750 mg oral ciprofloxacin twice daily from Day 2 through the morning of Day 9).
Across all three studies, 320 subjects received one or more 16 mg/kg doses of Anthim intravenously. Pruritus, rash, cough, infusion site swelling, urticaria, and injection site pain were the most frequently reported adverse events considered at least possibly related to the administration of Anthim. Two serious adverse events were reported in subjects who received Anthim: one case of ovarian cyst in Study AH104, and one case of ankle fracture in Study AH109. Neither of these events were considered related to the administration of Anthim. The combination of Anthim and ciprofloxacin was well tolerated in the 20 subjects who received both drugs in Study AH110. There were no deaths reported during any of the three studies.
Hypersensitivity reactions and anaphylaxis were the main safety concerns. These risks were highlighted in a Serious Warnings and Precautions box in the Anthim Product Monograph, along with instructions for proper administration and monitoring. Clinical symptoms of hypersensitivity were reported in 30 subjects (9.4%) who received Anthim and in four subjects (5.7%) who received placebo, and include pruritus, cough, urticaria, rash, anaphylactic reaction, chest discomfort, dermatitis, flushing, cyanosis, and dyspnea. One subject reported anaphylaxis (Study AH104). Pre‑medication with diphenhydramine, an antihistamine, is recommended prior to the administration of Anthim.
Discontinuation of Anthim due to hypersensitivity reactions was reported for 8 out of 250 subjects who received a single dose (Studies AH104 and AH110). Additionally, 2 out of 70 subjects in the repeat administration study (AH109) discontinued due to concerns about hypersensitivity reactions that could recur with the second administration of Anthim.
Mean values for electrocardiogram parameters remained stable over time, and were similar for subjects who received Anthim and those who received placebo. Prolongation of the QT interval was not observed with either single or repeat doses of Anthim.
As with any therapeutic protein, immunogenicity (the development of anti‑drug antibodies [ADAs]) may occur. Fourteen out of 470 subjects (3%) who received Anthim intravenously developed ADAs. The presence of ADAs did not appear to have an impact on Anthim disposition, and no adverse events were coincident with the development of an ADA response in any of these subjects.
Follow‑up for healthy subjects in the clinical safety studies continued for up to 190 days post‑dosing. Long‑term safety data were not available at the time of authorization, and there are no post‑market data as Anthim is not commercially available in any countries.
Although safety studies were not conducted in pediatric patients (<18 years of age), a pediatric indication has been approved based on population pharmacokinetic data due to the deadly nature of inhalational anthrax. Recommended doses for pediatric patients are based on body weight.
For more information, refer to the Anthim Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Due to the severe and life‑threatening nature of inhalational anthrax, it is not ethical or feasible to conduct human clinical trials to evaluate the efficacy of the drug. Evidence of the efficacy of Anthim comes from non‑clinical studies. Safety studies were conducted in healthy adult human volunteers, and are described in the Clinical Safety section.
The therapeutic effect of obiltoxaximab, the medicinal ingredient in Anthim, depends on its ability to bind the protective antigen (PA) of Bacillus anthracis. The binding of obiltoxaximab to the PA was observed in three in vitro studies. The neutralizing ability of obiltoxaximab was also demonstrated in an in vitro lethal toxin neutralization assay.
Efficacy Studies
In vivo efficacy studies were conducted in New Zealand White (NZW) rabbits and cynomolgus monkeys, including trigger‑to‑treat studies, pre‑ and post‑exposure prophylaxis studies, and combination studies. The main primary endpoint was the survival rate at Day 28 post‑exposure.
Trigger‑to‑treat studies evaluated the treatment with Anthim after infection had been established in animals, as evidenced by the presence of protective antigen in the circulation and the development of fever. The treatment was delayed (a range of 26‑40 hours delay) to allow disease to be established. Four trigger to treat studies (two in rabbits and two in monkeys) were conducted to evaluate the efficacy of Anthim administered intravenously. The results showed that a single dose of Anthim at a dose level of 16 mg/kg increased the survival rate (31% to 93%) compared to placebo group (0% to 6%).
The efficacy of Anthim in combination with antibiotics (levofloxacin, ciprofloxacin, doxycycline) was also evaluated in the animal models of inhalational anthrax. These combinations resulted in higher survival outcomes than antibiotic therapy alone based on multiple studies in which Anthim and antibiotics were administered at various doses and treatment times.
Overall, the animal studies demonstrated the efficacy of Anthim at a dose level of 16 mg/kg administered intravenously as monotherapy or in combination with antibiotics in the treatment of inhalational anthrax in monkeys and rabbits.
The post‑exposure prophylaxis studies evaluated Anthim for prophylaxis at several time points after animal exposure to B. anthracis spores. In one study in cynomolgus monkeys, 16 mg/kg Anthim was administered by intramuscular injection at 18, 24, or 36 hours after spore challenge. Survival rates at Day 28 were 100% (6/6), 83% (5/6), and 50% (3/6) in the groups that received treatment after 18, 24, and 36 hours, respectively.
One pre‑exposure prophylactic study evaluated Anthim for prophylaxis at several time points prior to animal exposure to B. anthracis spores. A 16 mg/kg intramuscular injection was administered to cynomolgus monkeys at 24, 48, or 72 hours prior to spore challenge. Survival rates at Day 56 were 100% (14/14) in each group.
Anthim is not indicated for pre‑exposure prophylaxis, as the duration of the protection provided by Anthim is unclear. Anthrax spores release toxins when activated. While spores are usually activated after 1‑6 days, some spores can remain dormant in the body and may take 60 days or more to be activated. Although an indication for pre‑exposure prophylaxis is not acceptable, Anthim is indicated for post‑exposure prophylaxis when alternative therapies are not available or not appropriate.
Safety Studies
Cardiovascular function was evaluated in two safety pharmacology studies in cynomolgus monkeys. A dose‑related increase in blood pressure and prolonged QT interval were observed in one study, but not in the other. Central nervous system lesions were observed in anthrax‑infected non‑surviving animals in the groups that received Anthim (≥4 mg/kg) as well as in the control groups. No dose‑response relationship was identified with respect to brain histopathology. No treatment‑related brain lesions were detected in anthrax‑infected surviving NZW rabbits at Day 28 after single doses up to 16 mg/kg, or in cynomolgus monkeys up to Day 56 after doses up to 32 mg/kg. Hemorrhage or hemorrhagic meningoencephalitis were observed in surviving animals treated with Anthim as well as surviving animals in the control group. These effects were therefore not considered related to treatment. No neurobehavioral effects related to Anthim were observed in surviving anthrax‑infected cynomolgus monkeys following treatment.
Repeat‑dose toxicity studies were conducted in rats and cynomolgus monkeys for up to 14 days. A toxic dose was not achieved in rats and monkeys administered doses up to 30 mg/kg. One pilot study was conducted in rats, in which the maximum tolerated dose was not reached with doses up to 100 mg/kg. No prolongation of the QT interval was observed in monkeys.
An embryonic‑fetal development study was conducted in which doses of Anthim up to 32 mg/kg (corresponding to approximately twice the human dose) were administered to pregnant, healthy NZW rabbits. Four doses were administered intravenously on gestation days 6, 10, 13, and 17. No evidence was observed of maternal toxicity or adverse reproductive or developmental effects in the fetuses.
Local tolerance was assessed in rabbits and monkeys through a single intramuscular injection of Anthim. In rabbits, no test article‑related histopathological findings were observed at the injection site. In monkeys, minimal to mild chronic inflammatory lesions were observed at the injection site.
The neuropathology of Anthim was assessed in rabbits and monkeys exposed to anthrax, and in healthy uninfected rabbits. No treatment‑related neuropathological effects were observed. Hemorrhage or hemorrhagic meningoencephalitis were observed in surviving animals treated with Anthim, as well as in surviving animals from the control group and the group that received levofloxacin alone. Therefore, this effect is not considered to be related to Anthim. It also showed that Anthim could not always protect against anthrax‑related meningitis.
Dedicated genotoxicity and carcinogenicity studies were not conducted for Anthim.
For more information, refer to the Anthim Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Substance
Detailed characterization studies were performed to provide evidence that obiltoxaximab, the drug substance, consistently exhibits the desired structure and properties (physical, chemical, and biochemical). These studies also demonstrated that the drug substance meets biological activity and purity standards for an active substance in a medicinal product.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Obiltoxaximab, the drug substance, is an affinity‑enhanced, de‑immunized, chimeric (human‑murine) monoclonal antibody designed to target the protective antigen (PA) of Bacillus anthracis. It is produced in stably transfected GS‑NS0 myeloma cells, which have been engineered to express obiltoxaximab through recombinant deoxyribonucleic acid (DNA) technology.
Drug substance manufacturing begins with the initiation of a culture of cells expressing obiltoxaximab from a single working cell bank vial. The cell culture is transferred to progressively larger vessels as it expands and the cells secrete the drug substance into the culture medium. The cell culture undergoes centrifugation and filtration. The clarified cell culture supernatant (which contains the drug substance) is purified through a series of viral inactivation, chromatography, and filtration steps, and undergoes buffer exchange into the final formulation buffer. The resulting solution is concentrated to the target concentration, and final excipients are added. The drug substance is sterile filtered into storage containers and stored below ‑20°C.
The drug product, Anthim, is produced by thawing, pooling, and mixing drug substance lots, and combining the pooled drug substance with a dilution and formulation buffer. The solution undergoes bioburden reduction and sterile filtration, and is aseptically filled into vials. The vials are visually inspected and stored at 2‑8°C.
Changes to the drug substance and drug product manufacturing processes made throughout the pharmaceutical development are considered acceptable upon review.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of obiltoxaximab with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
Anthim is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.
Validation of the drug substance manufacturing process was achieved through the analysis of samples from consecutively manufactured drug substance lots, which met all release specifications. Additional supportive studies were conducted to evaluate in‑process hold times, reprocessing, resin and membrane re‑use and cleaning, mixing, shipping, and viral clearance. The manufacturing process is maintained in a validated state through a continued process verification program.
Validation studies of the drug product manufacturing process demonstrated that it consistently yields drug product which meets quality attributes related to identity, strength, purity, potency, and safety. The drug product is tested against suitable reference standards to verify that it meets the relevant specifications. Analytical methods performed at multiple sites were validated independently at each manufacturing site and found to be comparable between sites.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 84‑month shelf life at 2‑8°C is considered acceptable for Anthim.
Facilities and Equipment
Although on‑site evaluations (OSEs) were originally recommended, it was not feasible to conduct them during the review cycle due to scheduling constraints. The suitability of the facilities to manufacture Anthim was adequately assessed through the review of reports from recent inspections conducted by the United States Food and Drug Administration (FDA). The results of this assessment indicated that the facility and processes were suitable for the production of Anthim.
Adventitious Agents Safety Evaluation
The master and working cell banks were evaluated according to International Council for Harmonisation (ICH) guidelines. Test results indicate that they are free from adventitious agents and suitable for the production of the drug substance.
An adequate microbial control strategy has been implemented, including bioburden and endotoxin monitoring. A virus reduction study was performed in line with ICH guidelines using qualified scaled‑down models. The results demonstrated that the process is capable of reducing viral contaminants such that detected levels are below the acceptable limits.
Raw materials used in the manufacture of Anthim are controlled throughout their life cycle (from procurement to disposal) to ensure that potential sources of impurities or adventitious agents can be identified. The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.