Background Analysis: US FDA Advisory Committee to Review Pathways to Develop Monoclonal Antibodies for Use in Rabies Post-Exposure Prophylaxis– APR 25, 2019 (AMDAC)

Announcement

The US FDA has scheduled an Antimicrobial Drugs Advisory Committee (AMDAC) meeting for Thursday, April 25, 2019. The committee will discuss pathways for approval of rabies virus monoclonal antibodies for use as the passive-immunization component of post-exposure prophylaxis.

Indication Background

The threat to public health of human infection with the rabies virus is mostly caused by transmission of the virus from infected dogs and bats to humans. If left untreated, infection with the rabies virus can cause fatal encephalitis. In 2015, animals infected with the rabies virus (N=6,508) were reported in all US states except for Hawaii, and three cases of transmission to humans were reported.

Pre-exposure vaccination

Pre-exposure rabies vaccination is typically considered for at-risk groups, including veterinarians and their staff, animal handlers, rabies researchers, certain laboratory workers and international travelers, and other people whose activities bring them into frequent contact with the rabies virus or potentially rabid animals.

Two rabies vaccines containing inactivated rabies virus are US-licensed: Imovax, which is manufactured by Sanofi Pasteur; and RabAvert, which is manufactured by Novartis. Vaccination typically consists of 3 intramuscular doses, one injection per day on days 0, 7, and 21 or 28.

Postexposure Prophylaxis

Postexposure prophylaxis (PEP) involves local infiltration of the related wound with rabies immune globulin (RIG), followed by vaccination. The use of RIGs is a type of passive immunization. RIG products are obtained through extracting immune globulin that is produced in human or equine blood subsequent to administration of rabies vaccine. In general, human RIG (or HRIG) is preferred over equine RIG (or ERIG), due to ERIG’s association with development of serum sickness, at an estimated rate ranging from 1 to 3% of recipients.

Three HRIGs are currently US-licensed: KEDRAB, which is manufactured by Kamada Ltd.; HyperRAB, which is manufactured by Grifols; and Imogam, which is manufactured by Sanofi Pasteur.

Recent rabies research has advanced an alternative approach to the use of RIGs as the passive immunization component of PEP. Monoclonal antibodies (rabies mAbs) that are not extracted from human or equine blood are being explored as alternatives to RIGs.

Rabies mAb “cocktails” that have reached the clinical development stage include candidates by the following companies: Zydus Cadila, in collaboration with the World Health Organization (WHO); Synermore Biologics; and North China Pharmaceutical Company, in collaboration with Molecular Targeting Technologies.

Regulatory Background

US Regulatory Background

On July 17, 2017, the FDA convened a public workshop on the topic of rabies mAbs. The objectives were to review developmental challenges and identify scientific work that can advance the field. Tarius expects that the briefing materials for the upcoming AMDAC meeting will present a summary of learnings from this workshop. We also anticipate that the questions to the AMDAC will likely mirror those raised at the workshop, which were as follows:

·      What can be learned from animal data, serologic data, and other clinical data from the WHO, Industry, and Academia?

·      What is the nature and strength of data supporting direct links between any specific in vitro, animal, or serologic assessments and contribution of a specific component and dose of PEP to human clinical outcomes?

·      What are the research gaps in understanding the contribution of rabies mAb to the PEP regimen?

·      What are potential uses and limitations of possible clinical trial designs?

and

·      What are ethical considerations in rabies mAb trial designs?

The AMDAC’s input will be used to inform future FDA guidance on rabies mAb development.

The FDA has posted meeting materials from the rabies mAb workshop, including archived webcasts and presentations, at the following link: https://www.fda.gov/Drugs/NewsEvents/ucm540832.htm.

Of note, one of the workshop presentations summarized the challenges with clinical trials of rabies mAb.

Global Regulatory Background

In April 2018, the WHO issued a position paper on the topic of rabies vaccination and PEP. The WHO noted in this paper that rabies mAbs may have several advantages compared to RIGs. The possible advantages that were listed include: capacity for large-scale production with standardized quality; greater effectiveness; elimination of the use of animals in the production process; and a reduced risk of adverse events. The WHO also noted the 2017 licensure of a rabies mAb product in India, named Rabimabs. A presentation about this product was also made at the aforementioned FDA workshop, and the slides are posted at the following link: https://www.fda.gov/downloads/Drugs/NewsEvents/UCM566898.pdf .

The WHO’s paper is posted at the following link: http://apps.who.int/iris/bitstream/handle/10665/272371/WER9316.pdf?ua=1

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: none. Drug Name: none Drug Class: vaccine, monoclonal antibodies Indication: rabies viral infection

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.