Enterovirus B) Is a New Organism

EPA staff report Determining whether Echovirus 7 (Enterovirus B) is a new organism

March 2018

Advice to the Decision-making Committee on determination APP203537: – To determine whether the viral species Echovirus 7 (Enterovirus B) is a new organism for the purpose of the Hazardous Substances and New Organisms Act 1996

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EPA advice Application APP203537

Executive Summary and Recommendation

On 1 February 2018, the Environmental Protection Authority (EPA) formally received an application from a New Zealand medical doctor, Ulrich Doering, requesting a statutory determination regarding the new organism status of the viral species Echovirus 7 (now taxonomically classified as a strain of Enterovirus B). The applicant requested the determination because he wishes to import a non-genetically modified Echovirus 7 isolate that is prepared and sold as a cancer treatment called Rigvir.

We have reviewed the information in the determination request and other information provided by the applicant as well as other relevant published literature regarding Echovirus 7 and Enterovirus B in New Zealand. Based on this analysis, we recommend that Enterovirus B (and by extension, all of its serotypes, including Echovirus 7) should be determined to be not a new organism for the purpose of the Act.

EPA advice Application APP203537

Table of Contents

Executive Summary and Recommendation ...... 2

Table of Contents ...... 3

1. Introduction ...... 4

2. Rigvir cancer treatment ...... 4

3. Echovirus 7 taxonomy and evidence regarding its presence in New Zealand ...... 5

4. Recommendation ...... 7

5. Comments from agencies ...... 8

6. Effect on New Zealand’s international obligations ...... 8

7. References ...... 9

8. Appendix: Enterovirus summary 20090407, Dr Sue Huang, Institute of Environmental Sciences Research ...... 10

EPA advice Application APP203537

1. Introduction

Purpose of this document

1.1. This document was prepared by EPA staff in the New Organisms team to advise the HSNO Decision-making Committee delegated to determine whether Echovirus 7 (Enterovirus B) is considered a new organism for the purpose of the Hazardous Substances and New Organisms Act (1996) (the Act). This document discusses information provided by the applicant as well as other readily available sources. Application summary

1.2. Doctor Ulrich Doering, a physician, applied to the EPA to seek a determination under section 26 of the Act on the new organism status of Echovirus 7. Doctor Doering requested the determination because he wishes to import a non-genetically modified variant of Echovirus 7, known commercially as Rigvir, into New Zealand as a cancer treatment for one of his patients.

1.3. In his application, Dr Doering described the characteristics of Rigvir as a cancer treatment, as well as providing a table of epidemiological data from the Institute of Environmental Sciences Research (ESR), detailing the incidence of Echovirus 7 (among other serotypes, including members of Enterovirus A, C, and D, as well as Parechovirus) in New Zealand. This table was provided to the applicant by Dr Sue Huang of ESR, signed by her to verify that it is a true and correct record of ESR’s data regarding the incidence of this virus in New Zealand.

2. Rigvir cancer treatment

2.1. As stated in the Application, Rigvir is a non-genetically modified Echovirus 7 that is sold commercially as a treatment for melanoma. As described in more detail below, Echovirus 7 is one of more than 50 serotypes of Enterovirus B. The development of Rigvir began in the 1960s and it was registered as a cancer therapy in Latvia in 2004 (Rigvir 2018). Latvian registration means that its registration is “grandfathered” in the European Union, because registration occurred prior to Latvia joining the EU in 2004.

2.2. Rigvir is described as an “adapted and selected ECHO-7 virus strain” (Alberts et al, 2016), developed and primarily sold and used in Latvia. Rigvir is a non-genetically modified Echovirus 7 (Donina et al, 2015), that was created by repeated passaging of

EPA advice Application APP203537

the virus in human tumour cell cultures (Chumakov et al, 2012). There are widely disparate views as to Rigvir’s effectiveness as a treatment for cancer, as well as the rigour of the studies used to evaluate it. For example, one review states that it is the “first enterovirus medication worldwide to complete the full cycle of clinical trials and to be applied in cancer therapy”, while another claims that there have been no double- blind studies for the safety and effectiveness of this treatment to date (Gorski 2017). Regardless of this ongoing debate, Medsafe, not the EPA, has the authority to consider the effectiveness of a medical treatment on a patient in its decision-making processes. Therefore, since Rigvir is not a GMO (and thus not a new organism on that criterion), the basis of the present determination is whether or not Echovirus 7 is a new organism in New Zealand. This issue is discussed in the following section.

3. Echovirus 7 taxonomy and evidence regarding its presence in New Zealand

Historical Background

3.1. Echoviruses are so named based on their serotypic (immune response profiles) and pathogenic characteristics, with the term ECHO being an acronym for Enteric (gut- derived) isolates, Cytopathogenic in tissue culture, Human origin, Orphan (not associated with a known clinical disease) (Pallansch et al, 2013). Echovirus 7 received its name as the seventh known serotype of this classification of virus.

3.2. The first taxonomic recognition of Echovirus 7 by the International Committee for the Taxonomy of Viruses (ICTV) was in its 3rd report in 1979. The summary document of the 3rd report on the ICTV website notes the classification of Echovirus 7 as a species in the family Picornaviridae, (order unassigned) genus Enterovirus, along with Echoviruses 1-6, 8, 9, 11-27, and 29-34.

3.3. This classification stood until the ICTV’s 7th report in 1999, when Echovirus 7 was reclassified, together with Human Coxsackieviruses A9, and B1-B6, in addition to Echovirus 1-6, 9, 11-21, 24-33, and 69, as a serotype of the new species Human Enterovirus B (Picornaviridae, Enterovirus).

EPA advice Application APP203537

3.4. The family Picornaviridae was assigned as a member of Class Picornavirales by the ICTV in 2008. The taxonomic classification of Order still has not been assigned to any genus of family Picornaviridae.

3.5. The species Human Enterovirus B was renamed simply Enterovirus B by the ICTV in 2012, on the basis that Human Enterovirus B species also infect such diverse animal species as Canis lupus familiaris (dog), Cercopithecus aethiops (vervet monkey), Pan troglodytes (common chimpanzee), Pongo pygmaeus (Orangutan), Rhinopithecus roxellana (Sichuan snub-nosed monkey) and Sus scrofa domesticus (domestic pig) (Knowles 2011).

3.6. Today, there are known to be at least 56 serotypes of Enterovirus B, which can cause a range of illnesses, ranging from minor febrile (fever) illness, chest and abdominal pain, diarrhoea, and meningitis, to acute flaccid paralysis (Pallansch et al, 2013). The Echovirus 7 serotype is not known to cause disease (Pallansch et al, 2013). Evidence for the presence of Enterovirus B (including Echovirus 7) in New Zealand

3.7. The applicant provided a table from the Institute of Environmental Sciences Research (ESR; see Appendix), signed by ESR scientist and Director of the World Health Organization National Poliovirus1 Reference Laboratory, Dr Sue Huang, certifying the table as a true and correct record of ESR’s detections of incidence of the Echovirus 7 serotype of Enterovirus B (among others). The table contains ESR’s records of Enterovirus detection from 1986 through 2008, spanning 23 years in total, both before and after 29 July 1998, the date the New Organisms provisions of the HSNO Act went into effect.

3.8. Closer examination of the table reveals the detection of 30 serotypes of Enterovirus B in New Zealand, including Echovirus 7. Specifically, these are: Coxsackieviruses A9, B1-B6, and Echoviruses 1-7, 9, 11, 13-21, 24-27, 30, and 33 (see Appendix). This includes the Echovirus 8 entry on the list, which was found to have been an incorrectly serotyped Echovirus 1 (Knowles et al, 2009). As can also be seen in the Appendix, all

1NB: Poliovirus comprises three specific serotypes of Enterovirus C, the type species of genus Enterovirus.

EPA advice Application APP203537

of these Enterovirus B serotypes have been recorded at least once by ESR in New Zealand after 1998, with four exceptions (Echoviruses 16, 17, 19, and 26).

3.9. The other Enterovirus species A, C, and D are also recorded on this list, as is Parechovirus A (As Echovirus 22 and 23 shown here before the reclassification of these viruses into the new species Parechovirus in 2011). It is notable that Polioviruses 1-3 (serotypes of species Enterovirus C, but eradicated in New Zealand) were not detected during the period of this record. Regardless, these other viral species are not the subject of this determination.

3.10. Echovirus 7 is among the more common Enterovirus B serotypes in New Zealand, with 81 total detections, and 38 detections after 1998. We take this information, and the information described in paragraph 3.8 as proof of the existence of Enterovirus B (particularly Echovirus 7) on 29 July 1998, and having an ongoing presence in New Zealand after that date.

4. Recommendation

4.1. A new organism is defined in section 2A of the Act, and includes: (a) An organism belonging to a species that was not present in New Zealand immediately before 29 July 1998:

4.2. The following Act criteria were not applicable to this determination as the four species under consideration in this application;  have not been prescribed as risk species (section 2A(1)(b));  have not been approved to be held in containment or released with controls (sections 2A(1)(c), (ca) and (cb));  are not genetically modified organisms (section 2A(1)(d)); and  have not been eradicated from New Zealand (section 2A(1)(e)).

4.3. Based on the ESR statement, we conclude that Enterovirus B (including Echovirus 7) was present in New Zealand on and immediately before 29 July 1998, and to have a continuing presence in New Zealand after that date. We therefore recommend that Echovirus 7 should be determined not to be a new organism (as Enterovirus B).

EPA advice Application APP203537

5. Comments from agencies

5.1. EPA staff advised Medsafe, the Ministry for Primary Industries (MPI), and the Department of Conservation (DOC) on receipt of the application, as the agencies most likely to have information or knowledge on Echovirus 7 in New Zealand. DOC noted that they had no comment on the application. Neither MPI nor Medsafe commented on the application.

6. Effect on New Zealand’s international obligations

6.1. EPA staff are not aware of any international obligations that may be affected by this determination.

EPA advice Application APP203537

7. References

Alberts P, Olmane E, Brokāne L, Krastiņa Z, Romanovska M, Kupčs K, Isajevs S, Proboka G, Erdmanis R, Nazarovs J and others 2016. Long-term treatment with the oncolytic ECHO-7 virus Rigvir of a melanoma stage IV M1c patient, a small cell lung cancer stage IIIA patient, and a histiocytic sarcoma stage IV patient-three case reports. APMIS 124(10): 896-904.

Chumakov PM, Morozova VV, Babkin IV, Baikov IK, Netesov SV, Tikunova NV 2012. Oncolytic Enteroviruses. Molecular Biology 46(5): 639-650.

Donina S, Strele I, Proboka G, Auzinš J, Alberts P, Jonsson B, Venskus D, Muceniece A 2015. Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study. Melanoma Research 25(5): 421-426.

Gorski D, 2017. Rigvir: Another unproven and dubious cancer therapy to be avoided. Retrieved 28 February 2018. https://sciencebasedmedicine.org/rigvir-another- unproven-and-highly-dubious-cancer-therapy-to-be-avoided/

Knowles N 2011. In the genus Enterovirus, family Picornaviridae, create 2 new species, named Enterovirus F and Enterovirus G, respectively, and rename 10 existing species. In: ICTV ed. 2011.018a,bV, International Committee on Taxonomy of Viruses.

Knowles NJ, Hovi T, Hyypiä T, King AMQ, Lindberg AM, Pallansch MA, Palmenberg AC, Simmonds P, Skern T, Stanway G and others 2009. Family: Picornaviridae In: ICTV ed. ICTV 9th Report (2011), ICTV.

Pallansch MA, Oberste MS, Whitton JL 2013. Enteroviruses: Polioviruses, Coxsackieviruses, Echoviruses, and Newer Enteroviruses. In: Knipe DM, Howley PM ed. Fields Virology. 6th ed. Sydney, Wolters Kluwer/Lippincott Williams & Wilkins. Pp. 490-530.

Rigvir, Rigvir.com, 2018. Rigvir - first oncolytic therapy. Retrieved 24 February 2018. http://rigvir.com/clinical-studies/

EPA advice Application APP203537

8. Appendix: Enterovirus summary 20090407, Dr Sue Huang, Institute of Environmental Sciences Research