New substances: risk assessment summary 18146

Official title: Risk assessment summary for NSN 18146: TG1050, for use as an investigational hepatitis B vaccine in humans

Introduction

Under the Canadian Environmental Protection Act, 1999 (CEPA), animate products of biotechnology (i.e. “living organisms”) not listed on the Domestic Substances List (DSL) are considered “new” to Canada. Information and data prescribed by the New Substances Notification Regulations (Organisms) [NSNR(O)] must be submitted before manufacture or import takes place, and the assessment is conducted by Environment and Climate Change Canada (ECCC) and Health Canada (HC). In other words, the Government of Canada must be notified before new living organisms are manufactured in or imported into Canada, and must assess their potential to harm human health and the environment.

TG1050 was notified prior to being imported for use in human clinical trials and was assessed according to the requirements for Schedule 1 of the NSNR(O), which applies to “manufacture or import of new micro-organisms for introduction anywhere in Canada” (which is the appropriate Schedule for human clinical trials).

Regulatory decision

Import of TG1050 is considered not to be harmful to human health or the environment for the intended use as an investigational vaccine for Hepatitis B infection. In addition, TG1050 is not anticipated to enter the environment in a quantity or under conditions that have or may have an immediate or long term harmful effect on the environment or its biological diversity, constitute or may constitute a danger to the environment on which life depends, or constitute or may constitute a danger in Canada to human life or health through this use.

After 27 August 2015, the manufacture or import of TG1050 could proceed in Canada.  This strain is eligible to be added to the Domestic Substances List, but, until such time that it is officially published in the Canada Gazette, it would still be considered a ‘new substance’ and subject to the NSNR(O).

Background

TG1050 is a genetically modified virus (human adenovirus type 5 “hAd5”) that is intended for use as a vaccine in patients with chronic Hepatitis B virus (HBV) infection. The modifications render the micro-organism incapable of replication and it is therefore not able to cause disease. The modifications also enable the virus to produce proteins that are similar to those produced by HBV during an infection. In the human body, TG1050 stimulates an improved immune response against HBV by producing large amounts of these proteins. As a result, the patient’s own immune system more effectively attacks the HBV, helping to clear the infection.

Hazard considerations

The potential human health and environmental hazards are considered low for the following reasons:

• A gene enabling the virus to replicate was removed, thereby reducing its ability to cause disease. This was shown in animal studies with TG1050 as well as in human studies using other hAd5 strains that were also incapable of replication.
• Addition of a gene combination trio (Core-Pol-Env, sourced from the core, polymerase and envelope genes in HBV), enables the virus to produce these HBV proteins. The resulting fusion protein lacks the toxic properties of the individual proteins produced by the naturally occurring HBV.
• These gene modifications are well characterized and are considered to be stable in the micro-organism.

The environmental hazard potential of TG1050 is considered to be low for the following reasons:

• The host range of the wild-type hAd5 is limited to humans and a few mammalian species (Wold and Horwitz, 2007). There is no evidence to suggest that it can infect aquatic or terrestrial plants, invertebrates or vertebrates.
• With the exception of humans, naturally occurring hAd5 is not known to cause disease in mammals or other terrestrial vertebrates in the environment. A similar human adenovirus capable of replication was also not able to cause disease in a wide range of wild, domestic and laboratory animals (Knowles et al., 2009; Fry et al., 2013).

The human hazard potential of TG1050 is considered to be low for the following reasons:

• Naturally occurring hAd5 is abundant in the environment. It can cause respiratory tract infections in humans that are usually mild and do not require treatment in healthy individuals.
• Similar hAd5 strains have been safely used in humans for gene delivery. In cancer studies, injections of high doses of other replication deficient hAd5 were well tolerated (Dummer et al., 2010; Khorana et al., 2003).
• In the unlikely event of infection with TG1050, effective antiviral drugs are available to treat hAd5 infections.

Exposure considerations

The environmental and human exposure potential of import and use of TG1050 for investigational use is considered to be low for the following reasons:

• TG1050 is not manufactured in Canada. lf it were, environmental exposure would not significantly increase, as the methods used for manufacturing TG1050 would require compliance with the Canadian Biosafety Standards and Canadian Biosafety Guidelines, which limit environmental release and exposure.
• Procedures are in place to minimize the environmental release of TG1050 during the clinical trial. The micro-organism will be administered at a clinical site under controlled conditions and all virus-containing wastes will be decontaminated.  In addition, there is a low potential for shedding of TG1050 following subcutaneous injection. Patients are also given instructions to help minimize the spread of any shed virus.
• The replication defect in TG1050 prevents its spread in the blood of infected individuals.
• TG1050 is unlikely to be used for anything other than the treatment of chronic Hepatitis B infection. A commercialized drug product could be administered in up to 265 patients per year in Canada.

Risk assessment conclusion

Risk is typically described as the probability of an adverse effect occurring based on hazards and a particular scenario of exposure (Environment Canada and Health Canada, 2011). Different exposure scenarios can be described based on intended and any potential uses. In the present case, the micro-organism will be imported and used as an investigational vaccine or as an approved and commercialized drug.

Given the low potential environmental hazard and the low potential environmental exposure, the environmental risk associated with the use of TG1050 used as an investigational vaccine is considered low.

Given the low potential human health hazard and the low potential human exposure, the human health risk associated with the use of TG1050 as an investigational vaccine for Hepatitis B infection is considered low.

Therefore, TG1050 is not anticipated to enter the environment in a quantity or under conditions that have or may have an immediate or long term harmful effect on the environment or its biological diversity, constitute or may constitute a danger to the environment on which life depends, or constitute or may constitute a danger in Canada to human life or health.

Should TG1050 be approved and commercialized for use in Canada as a vaccine for Hepatitis B infection, similar safety protocols as those used during the investigational use are expected to be followed and releases to the environment would not be expected from any manufacturing in Canada. The environmental and indirect human exposure is therefore not expected to change significantly, and so would not significantly increase environmental or human health risk.

References

(excluding proprietary information or references provided by the notifier)

Dummer, R., Eichmüller, S., Gellrich, S., Assaf, C., Dreno, B., Schiller, M., Dereure, O., Baudard, M., Bagot, M., and Khammari, A. (2010). Phase II Clinical Trial of Intratumoral Application of TG1042 (Adenovirus-interferon-γ) in Patients With Advanced Cutaneous T-cell Lymphomas and Multilesional Cutaneous B-cell Lymphomas. Molecular Therapy. 18, 1244-1247.

Fry, T.L., VanDalen, K.K., Duncan, C., and VerCauteren, K. (2013). The safety of ONRAB® in select non-target wildlife. Vaccine. 31, 3839-3842.

Khorana, A.A., Rosenblatt, J., Sahasrabudhe, D., Evans, T., Ladrigan, M., Marquis, D., Rosell, K., Whiteside, T., Phillippe, S., and Acres, B. (2003). A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma. Cancer Gene Therapy. 10, 251-259.

Knowles, M.K., Nadin-Davis, S.A., Sheen, M., Rosatte, R., Mueller, R., and Beresford, A. (2009). Safety studies on an adenovirus recombinant vaccine for rabies (AdRG1.3-ONRAB) in target and non-target species. Vaccine 27, 6619-6626.

Wold, W., and Horwitz, M. (2007). Adenoviruses. Fields Virology 2, 2395-2436.

Environment Canada and Health Canada (2011), "Framework for Science-Based Risk Assessment of Micro-Organisms Regulated under the Canadian Environmental Protection Act, 1999".