Executive Summary

AVI-6002 (Sarepta Therapeutics, Cambridge, MA, USA) is a drug in development intended to treat Ebola virus disease (EVD). According to the manufacturer, “AVI-6002 is an experimental combination of 2 phosphorodiamidate morpholino antisense oligomers [PMOs] with positive charges on selected subunits (PMOplus™).” The drug functions by interfering with RNA-signaling involved in protein synthesis. By altering protein synthesis, the drug can alter the molecular structure of viral bodies and thus potentially slow or halt the progression of disease.

Two PMOs—AVI-7537 and AVI-7539—originally composed the compound AVI-6002. However, after animal studies evaluating the efficacy of AVI-6002, the manufacturer determined that only one of the PMOs showed efficacy, and current formulations contain only the compound AVI-7537. Of note, the current literature describes the original combined formulation.

  • Our searches of PubMed, EMBASE, and selected web-based resources (see below) identified no published clinical evidence that addresses how well AVI-6002 treats EBV in infected human patients; human trials to date have tested the drug in heathy volunteers only.  
  • We base our opinion on review of results from two conference abstracts presenting preclinical data in animal models(1) and a phase I clinical safety study in healthy volunteers(3) and one abstract from a full published paper reporting phase 1 clinical safety and pharmacokinetic data.(2)  Evidence from conference abstracts should be interpreted with caution because they often focus more on positive results or present incomplete results. Preclinical data in nonhuman primates suggest that the drug is somewhat efficacious in animal models, with survival of approximately 60% of Ebola Zaire–infected rhesus macaques. While nonhuman primate models are appropriate for examining the efficacy of EBV treatments, research conducted in animals may have limited applicability to human use; therefore, the evidence should be considered with caution. In the phase I clinical trials, the authors report that the drug was well-tolerated up to doses of 6 mg/kg.  Side effects deemed to be treatment related were reported to be mild to moderate and included headache, nausea, and fatigue. The efficacy of AVI-6002 in treating EBV in humans has yet to be determined.

Who Should Read This

Table of Contents

Product Overview

AVI-6002 (Sarepta Therapeutics, Cambridge, MA, USA) is a drug in development intended to treat Ebola virus disease (EVD). According to the manufacturer, “AVI-6002 is an experimental combination of 2 phosphorodiamidate morpholino antisense oligomers [PMOs] with positive charges on selected subunits (PMOplus™).” The drug functions by interfering with RNA-signaling involved in protein synthesis. By altering protein synthesis, the drug can alter the molecular structure of viral bodies and thus potentially slow or halt the progression of disease (see link to the manufacturer’s website under Resources Searched).

Two PMOs—AVI-7537 and AVI-7539—originally composed the compound AVI-6002. However, after animal studies evaluating the efficacy of AVI-6002, the manufacturer determined that only one of the PMOs showed efficacy, and current formulations contain only the compound AVI-7537. Of note, the current literature describes the original combined formulation (see link to the manufacturer’s website under Resources Searched).

 

Purported Benefits/Advantages According to Manufacturer’s Information*

  • “Our RNA therapeutics direct the cellular machinery involved in making proteins. These drugs can be designed to increase or decrease the production of a protein involved in a disease.”
  • “PMOs are charge-neutral, which reduces off-target interactions with proteins in the body that have led to immune stimulation and kidney toxicity with other RNA chemistries.”
  • PMOs are highly resistant to degradation by enzymes, which prolongs drug activity.”
  • “PMOs can be combined in a modular fashion to rapidly design and construct drug candidates that are specific for human or pathogen RNA and can be targeted to specific tissues.”

*Note: This is a list of the main benefits described by the manufacturer and does not imply endorsement or validation by ECRI Institute. We list them to identify for the reader the areas about which we will search for evidence.

 

Regulatory Status

Sarepta Therapeutics received funding to conduct phase I clinical trials on AVI-6002 in 2011 from the U.S. Department of Defense through the Joint Project Manager Transformational Medical Technologies program. This program is intended to function as a fast-track program to develop treatments that will "protect the Warfighter from emerging, [which is] genetically altered and unknown biological threats" (see link to the manufacturer's website under Resources Searched). However, funding for the project was “terminated for convenience of the Government due to funding constraints” (see ClinicalTrials.gov link to “A Study to Assess…” under Recourses Searched.) As of November 2014, no information is available regarding the status of a new drug application to the U.S. Food and Drug Administration (FDA) for AVI-6002.

FDA can grant emergency expanded access for use of investigational drugs to patients with serious or immediately life-threatening diseases within a very short period (see link to the FDA document on compassionate use in Resources Searched)). It is not clear from our searches whether Sarepta has begun the process of applying for expanded access (as of November 2014).

In August 2014, the World Health Organization (WHO) convened a panel of medical ethicists to address concerns about use of untested therapies in patients with EVD. The panel concluded that “in the particular context of the current Ebola outbreak in West Africa, it is ethically acceptable to offer unproven interventions that have shown promising results in the laboratory and in animal models but have not yet been evaluated for safety and efficacy in humans as potential treatment or prevention.” The panel further emphasized that “researchers have a moral obligation to collect and share all the scientifically relevant data generated from treatments provided for compassionate use.” For more information, see link to the WHO report on ethical considerations in Resources Searched. 

Background on Ebola

Ebola virus is one of many types of viruses that cause hemorrhagic fever and, along with Marburg virus, is part of the Filoviridae viral family. Ebola is an enveloped RNA virus, meaning that the RNA and protein shell (capsid) of the virus are covered (enveloped) in a coat of fatty acids (lipids). This lipid layer is gained when the virus enters or “buds” into a host cell. Enveloped viruses differ structurally from nonenveloped viruses, and these differences have important implications for disinfection protocols, discussed briefly below (see links to the Medscape article by Saemi and the chapter on virology by Hunt under Resources Searched). For Ebola infection to occur, an individual must be exposed directly to bodily fluids from an infected host (either animal or human) (see link to the article on Transmission from the U.S. Centers for Disease Control and Prevention [CDC] under Resources Searched).The virus enters the new host through contact with mucus membranes, such as the eyes or nose, or through broken skin, such as through a cut or needlestick.

Although under ideal conditions, the virus could persist up to six days on surfaces; in hospital conditions, with daily cleaning and disinfection, the virus more likely would survive in patient areas for a day or less (see link to CDC’s Interim Guidance for Environmental Infection Control under Resources Searched). Despite this uncertainty, current CDC recommendations for cleaning and disinfecting potentially contaminated surfaces in patient areas err on the side of caution. Depending on the virus strain, the individual’s immune response, waiting time for treatment, and access to quality healthcare, mortality for those infected with Ebola ranges from about 25% to 100%, averaging approximately 50% (see link to the Medscape article by Saemi under Resources Searched).

The 2014 Ebola outbreak in West Africa is noted as the worst known outbreak and is a global public health concern. CDC estimates suggest that cases are doubling in Liberia every 15 to 20 days, and cases in Sierra Leone and Guinea are doubling every 30 to 40 days. CDC projections through January 20, 2015, range from 500,000 to nearly 1.5 million potential cases in Liberia and Sierra Leone. As of late October, nearly 10,000 cases were recorded and more than 4,500 people had died from the infection in West Africa, which is more than all previous Ebola outbreaks combined (see links to CDC’s Questions and Answers: Estimating Future Number of Cases under Resources Searched).

According to CDC and the World Health Organization (WHO), after direct exposure, symptom onset begins in 2 to 21 days; average time to onset is 8 to 10 days. Importantly, a person is infectious only if symptomatic. However, the long incubation period means that an individual may have travelled a long distance from the initial point of infection, thus increasing the likelihood that the virus could spread to a wider area. Countries and states are examining travel requirements and instituting varying restrictions on travelers from West African countries. (See link to CDC press release on postarrival monitoring for travelers to the United States and link to the New England Journal of Medicine’s interactive Ebola Virus Disease: Current Knowledge under Resources Searched.)

Diagnosis and Prevention

Symptoms of EVD have a sudden onset, typically including fever, fatigue, muscle pain, headache, and sore throat. Subsequent symptoms include vomiting, diarrhea, rash, and liver and kidney impairment. Bleeding from internal and external sites such as the eyes and gums—thought of as the prototypical sign of EVD—is not evident in all individuals with the virus (see link to WHO’s Ebola Fact Sheet under Resources Searched). Most symptoms are nonspecific, so definitively attributing symptoms to EVD is difficult. According to WHO, confirming EVD symptoms is done using the following investigations:

  • Antibody-capture enzyme-linked immunosorbent assay
  • Antigen-capture detection tests
  • Serum neutralization test
  • Reverse transcriptase polymerase chain reaction assay
  • Electron microscopy
  • Virus isolation by cell culture

Preventing EVD depends on rigorous hygiene practices and avoiding touching a person or animal, living or dead, with the virus. To minimize risk of transmission, CDC recommends isolating or quarantining individuals who have had unprotected contact with an EVD host or the host’s bodily fluids (including meat from infected animals). Patients with probable or diagnosed EVD should be isolated from other patient areas and from each other. All individuals who come into contact with or enter the room of an individual with probable or confirmed EVD must have training and demonstrated competency in donning and removing personal protective equipment with full body coverage (see links to CDC Guidance on Prevention and Personal Protective Equipment under Resources Searched).

Current Ebola Treatments

In mid-November 2014, Doctors Without Borders announced it would be partnering with three groups to start three clinical trials in December 2014 in certain African countries to test two antiviral drugs and human plasma-containing Ebola antibodies (from recovered patients). The French National Institute of Health and Medical Research will test favipiravir at an Ebola treatment center in Guinea; the University of Oxford will test brincidofovir at a site that has not been chosen yet; the Antwerp Institute of Tropical Medicine will test how well patients with Ebola respond when given blood or plasma that contains antibodies from people who have survived the virus.

The only treatment for EVD has been supportive care that treats symptoms, administers fluids (either orally or intravenously) and electrolytes, and treats secondary infection. This care can improve survival, and the earlier a patient receives treatment, the better the prognosis. In addition to Sarepta’s RNA-based therapeutics, several other potential treatments are under investigation, including antiviral medications, monoclonal antibodies, and blood purification (see links to ECRI Institute’s related publications under Resources Searched).

At the time of this Product Brief, no preventive vaccines are available for Ebola (see links to the CDC document titled Treatment and WHO’s Ebola Fact Sheet under Resources Searched). We identified five clinical trials registered with Clinicaltrials.gov (recruiting and not yet recruiting): four are investigating vaccines, and one is investigating the antiviral medication brincidofovir (see links to ClinicalTrials.gov entries under Resources Searched).

Environmental Safety

Enveloped viruses such as Ebola are infectious only as long as the lipid envelop remains intact. Disinfectants, alcohols, and detergents that break down the lipid layer can inactivate the virus. Nonenveloped viruses do not have this lipid layer and require stronger disinfecting agents. Current recommendations are that stronger disinfectants (those that are effective against the more resistant nonenveloped viruses) be used in areas that may be contaminated with Ebola virus (see links to the CDC Interim Guidance for Environmental Infection Control and the chapter on virology by Hunt under Resources Searched).

See ECRI Institute's Ebola Resource Center for links to the latest company publications on EVD.

Clinical Literature

We searched PubMed, EMBASE, and selected web-based resources for documents relevant to this topic and published between January 1, 2009, and October 31, 2014. We did not identify any papers that addressed the use of AVI-6002 in patients with EVD. We identified one conference abstract that described preclinical data on the effectiveness of treating Ebola virus in both rodent and nonhuman primate models.(1) In this report, AVI-6002 effectively treated Ebola virus in 60% to 63% of nonhuman primates. We also identified one abstract from a full published paper(2) and one conference abstract(3) assessing the safety and tolerability of AVI-6002 in healthy human participants. These abstracts reported that AVI-6002 was well-tolerated in doses up to 6 mg/kg (although one trial planned to administer a dose of 9 mg/kg, those data were not yet available in the abstract).

Safety

We also searched ECRI Institute’s Health Devices Alerts database for product-specific alerts or recalls. We did not identify any relevant information.

Table 1. Product-specific Clinical Literature
Author/Year Study Type and Patients Treatment(s) Results as Reported by Authors Authors' Conclusions
Full Papers
Heald et al. 2014(2)

Pharmacokinetic and safety trial of AVI-6002 in 30 participants.

Note: AVI-6003, which is targeted for Marburg virus, was also tested in this paper.

AVI-6002 (0.005, 0.05, 0.5, 1.5, 3.0, and 4.5 mg/kg) given intravenously in 150 ml saline over 30 minutes (n = 4 per dose).

vs.

Placebo: 150 ml saline given intravenously over 30 minutes (n = 6).

All doses of AVI-6002 were well tolerated, with no maximally tolerable dose observed. Plasma half-life was between 2 and 5 hours.

The safety profile between AVI-6002 and AVI-6003 were reported to be similar, but no other safety information is presented in the abstract.

No conclusions presented in the abstract.
Conference Abstracts

Heald et al. 2012(3)

 

 

Phase I safety trial of AVI-6002 in 30 participants (data for first 25 participants included in the abstract)

 

AVI-6002 (0.01, 0.1, 1.0, 3.0, 6.0, and 9.0 mg/kg) given intravenously (data for 9 mg/kg not presented).

vs.

Placebo: saline given intravenously

Adverse events were reported in 14 participants. The majority were mild to moderate in severity (headache: n = 4; nausea: n = 3; fatigue: n = 2; other numbers not reported). 1 participant experienced severe hypertension that was deemed unrelated to exposure to AVI-6002."Preliminary results of this first-in-man phase 1 study suggest that single IV administrations of AVI-6002 are well-tolerated up to a dose level of 6 mg/kg. Follow-up of subjects enrolled in the 6th cohort (9 mg/kg) is ongoing. Final, unblinded safety and pharmacokinetic results for all subjects will be presented."
Warren et al. 2010(1)Basic laboratory study on AVI-6002 and AVI-6003 in filovirus-infected rodents (mouse and guinea pig) and non-human primates (rhesus macaque: n = 13).Various virus-specific compounds were tested in rodent models. Candidate compounds (including AVI-6002) were tested in nonhuman primates.AVI-6002 given intraperitoneally and subcutaneously (n = 8) or intravenously (n = 5) to macaques infected with Ebola-Zaire virus led to survival in 60%-63% of animals."AVI-6002 and AVI-6003 represent highly promising therapeutic candidates for treatment of filovirus infections in humans."

Glossary

Bibliography

References

Resource List

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Related Resources

ECRI Institute Resources

The following ECRI Institute reports also pertain to the Ebola virus. See ECRI Institute's Ebola Resource Center for links to the latest publications.

References Reviewed (PubMed and EMBASE were searched)

  1. Warren, T, Warfield, K, Wells, J, Swenson, D, Lovejoy, C, Iversen, P, and Bavari, S. Treatment of highly pathogenic filovirus infections using advanced antisense technology. Retrovirology. 2010;7 Suppl. 14. 16th International Symposium on HIV and Emerging Infectious Diseases;Marseille, France. EMBASE
  2. Heald, AE, Iversen, PL, Saoud, JB, Sazani, P, Charleston, JS, Axtelle, T, Wong, M, Smith, WB, Vutikullird, A, and Kaye, E. Safety and Pharmacokinetic Profiles of Phosphorodiamidate Morpholino Oligomers with Activity against Ebola Virus and Marburg Virus: Results of Two Single-Ascending-Dose Studies. Antimicrob Agents Chemother. 2014;58(11):6639-6647. PubMed 25155593 [PMID]
  3. Heald, A, Axtelle, T, Thimmarayappa, J, and Smith, W. A phase 1, single ascending-dose study of AVI-6002, a combination of two PMOplusTM compounds with activity against ebolavirus. Clinical Microbiology and Infection. 2012;18 Suppl. 3221. 22nd European Congress of Clinical Microbiology and Infectious Diseases;London, United Kingdom. EMBASE

U.S. Food and Drug Administration (FDA) Website

We identified no relevant drug approvals. We did identify the following information on compassionate use of drugs and devices.

Manufacturer Website (Sarepta Therapeutics, Cambridge, MA, USA)

ClinicalTrials.gov

We identified one withdrawn trial and one completed trial.

Additional Resources

Topics and Metadata

Topics

Medication/Drug Safety; Treatment of Disease

Caresetting

Emergency Department; Hospital Inpatient; Physician Practice

Clinical Specialty

Emergency Medicine; Infectious Disease

Roles

Allied Health Personnel; Clinical Practitioner; Pharmacist; Public Health Professional

Information Type

Guidance

Phase of Diffusion

 

Technology Class

Pharmaceutical

Clinical Category

 

UMDNS

SourceBase Supplier

Product Catalog

MeSH

​Disease Outbreaks
Drugs, Investigational/therapeutic use
Hemorrhagic Fever, Ebola/diagnosis/drug therapy/prevention & control
Humans
Morpholinos/therapeutic use
Oligonucleotides, Antisense
Viral Envelope Proteins/drug effects

ICD9/ICD10

FDA SPN

SNOMED

Ebola virus disease (37109004)
Viral envelope (115427003)

HCPCS

Disease/Condition

 

Publication History