Safety Assessment of World s First Novel Cocktail of Two Monoclonal Antibodies in WHO Category III Animal Bite Patients at Maulana Azad Medical College, New Delhi, India

Research Article

J Fam Med. 2024; 11(4): 1362.

Safety Assessment of World’s First Novel Cocktail of Two Monoclonal Antibodies in WHO Category III Animal Bite Patients at Maulana Azad Medical College, New Delhi, India

Agarwal A¹; Agarwal A²; Mohan A¹; Dutta T³*; Mahajan M³; Desai S³; Kumar D¹

11Department of Paediatrics, Maulana Azad Medical College, New Delhi, India

22Hindu Rao Hospital, Delhi, India

33Department of Vaccines, Zydus Lifesciences Ltd, Ahmedabad, India

*Corresponding author: Trayambak Dutta Department of Vaccines, Medical Advisor, Zydus Lifesciences Ltd, Ahmedabad, India. Tel: 8939719805 Email: [email protected]

Received: March 06, 2024 Accepted: April 23, 2024 Published: April 30, 2024

Abstract

Background: Rabies, a zoonotic disease, poses a significant global public health challenge, and Post-Exposure Prophylaxis (PEP) is crucial for prevention. Monoclonal Antibodies (mAbs) have emerged as a promising alternative to Rabies Immunoglobulins (RIGs) due to their high efficacy and standardized manufacturing process.

Materials & Methods: A prospective, open-label post-marketing surveillance study was conducted at, Maulana Azad Medical College (MAMC), New Delhi on patients with WHO category III suspected rabid animal bites. TwinRabTM, a novel cocktail of docaravimab and miromavimab, was administered at a dosage of 40 IU/kg in and around the wound, along with the Anti-Rabies Vaccine (ARV). Adverse Events (AEs) were graded using FDA Toxicity grading.

Results: In this study, 200 subjects received TwinRabTM with a 100% completion rate. Three (1.5%) patients showed solicited local AEs, and two (1%) patients showed solicited systemic AEs, which were resolved after appropriate treatment intervention. The overall tolerability assessment showed positive ratings from doctors (94%) and patients (74%).

Conclusion: The post-marketing surveillance study demonstrated the safety of TwinRabTM in patients who experienced Category III suspected rabid animal bites, thereby supporting its potential as an alternative option for the post-exposure prophylaxis in the management of animal bite for the prevention of rabies.

Keywords: Rabies; Post-exposure prophylaxis; TwinRabTM; Safety assessment; Adverse events.

Abbreviations: AEs: Adverse Events; ARV: Antiretroviral; CRFs: Case Report Forms; DALYs: Disability-Adjusted Life Years; EAPC: European Association of Political Consultants; EDC: Electronic Data Capture; ERIG: Equine Rabies Immunoglobulin; FDA: Food and Drug Administration; HRIG: Human Rabies Immunoglobulin; ID: Infectious Diseases; mAbs: Monoclonal Antibodies; PEP: Post-Exposure Prophylaxis; RIGs: Rabies Immunoglobulins; SAEs: Serious Adverse Events; TEAEs: Treatment-Emergent Adverse Events; WHO: World Health Organization

Introduction

Rabies, a viral disease transmitted through animal bites, lurks as a silent threat in over 150 countries. This near-fatal infection infiltrates the central nervous system, causing excruciating symptoms and ultimately death if left untreated [1]. Though preventable through vaccination, rabies claims thousands of lives annually, primarily children in Asia and Africa [2]. The majority of human rabies transmissions, approximately 99%, are due to exposure to infected dogs, resulting in fatal outcomes [1]. According to the National Center for Disease Control, in 2019, global rabies-related Disability-Adjusted Life Years (DALYs) were 782,052.30, which was 45.4% in 1990, and their Estimated Annual Percentage Change (EAPC) was -0.55% [3]. Rabies is a significant public health issue, causing around 59,000 deaths each year worldwide [4]. Dogs cause most of human infections, emphasizing the importance of widespread dog immunization initiatives [1]. Individuals under the age of 15 are the most affected by this catastrophe, making up 40% of the victims [3]. India is a significant global hotspot, accounting for 36% of worldwide deaths, with an estimated 18,000-20,000 fatalities annually [4]. Underreporting and misdiagnosis exacerbate the situation, indicating that the actual burden could be greater [5]. The economic cost amounts to US$8.6 billion yearly, but the human cost is incalculable [6]. The data highlights the critical necessity for enhanced initiatives in dog vaccination, public awareness campaigns, and better access to post-exposure prophylaxis to achieve a rabies-free future [7].

The World Health Organization (WHO) recommends post-exposure prophylaxis (PEP) for category II exposure involves vaccination only, and for rabies endemic countries, even this turns out to be a significant cost [8]. Recently, this cost has been minimized by using the updated Thai Red Cross Intradermal Regimen instead of the Essen intramuscular Regimen, which is predominantly used in Asia and recently also in India [9]. The World Health Organization (WHO) categorizes animal bites based on their severity and potential for rabies transmission: Category I (No exposure): Touching or feeding animals, licks on intact skin. Category II (Minor exposure): Nibbling of uncovered skin, minor scratches or abrasions without bleeding. Category III (Severe exposure): Single or multiple transdermal bites or scratches, licks on broken skin, mucous membrane contact with saliva [10]. The WHO recommendation for PEP of category III exposures consists of both rabies vaccine and rabies immunoglobulins (RIGs). RIGs are limited to only those individuals who have not been previously treated with vaccine [11].

There are two types of serum-derived RIGs (human [HRIG] and equine [ERIG]) that have been available for decades, and recently, one humanized Monoclonal Antibody (mAb) based RIG has been licensed in India [12]. WHO points out that around 25% exposures need to be given RIGs in endemic countries, but less than 1% end up receiving it [13].

In India and Thailand, only 2–3% of category III animal bite victims receive RIGs as part of PEP [14]. This is because these RIGs are available at high cost only and are always in limited supply; having been derived from serum, they are associated with the risk of blood-borne pathogens; furthermore, horse-derived RIGs have also been associated with anaphylactic reactions and serum sickness, which lately have been minimized by the use of Fragment Crystallizable (Fc)-deleted ERIG preparations [14]. In India, ERIG is used more frequently because it is less expensive than HRIG. These serious limitations have led WHO to recommend the development of alternative therapies [15].

Despite the availability of vaccines and immunoglobulins for rabies prevention, these treatments are often inaccessible to those in need, particularly in regions with limited access to medical care [16]. Furthermore, the current vaccines have limitations, including barriers to adherence to recommendations, confusion about risk categories, and noncompliance with recommendations for repeated titre checks [17].

A novel approach called TwinRabTM has been developed to address the challenges of rabies prevention. TwinRabTM is a combination of two monoclonal antibodies, docaravimab and miromavimab, which are mouse monoclonal antibodies targeting specific epitopes within antigenic sites II and III of the rabies virus glycoproteins [18]. Extensive preclinical and clinical studies have demonstrated the safety and non-inferiority of TwinRabTM to HRIG (Human Rabies Immunoglobulin) in terms of protective effect [18]. It has been approved for use in India and is considered a significant advancement in the field of rabies prevention, offering a promising alternative to existing treatments [18].

A Phase 3, Randomized, Open-label, Noninferiority Trial evaluated the safety and efficacy of the TwinRabTM (cocktail of monoclonal antibodies Docaravimab & Miromavimab) in patients with WHO category III exposure from suspected rabid animals [19]. The study confirmed that TwinRabTM is non-inferior to HRIG in terms of providing an unbroken window of protection up to day 84 [19]. The responder rates for TwinRabTM and HRIG were 90.21% and 94.37% in the per-protocol population, respectively [19]. The Geometric Mean of RFFIT titres on day 14 were 4.38 and 4.85 IU/mL for TwinRabTM and HRIG, respectively [19].

The present study was conducted to assess the safety of the TwinRabTM (cocktail of monoclonal antibodies Docaravimab & Miromavimab) in category III animal bite patients. The initial findings emphasize the vital significance of examining safety parameters in real-world scenarios and significantly improving our understanding of the intervention's safety profile beyond the controlled conditions of Phase III trials.

Materials and Methods

Study Design

In this open-label post-marketing surveillance study, the safety of the cocktail of monoclonal antibody Docaravimab & Miromavimab (TwinRabTM) in combination with Anti-Rabies Vaccine (ARV) was assessed in patients who received treatment for Category III animal bite at Maulana Azad Medical College, New Delhi. The study was approved by the institutional ethics committee and was conducted in accordance with the Declaration of Helsinki and its subsequent revisions, Good Clinical Practice (GCP) guidelines, and other applicable local regulatory guidelines.

Objective

The objective of this study was to assess the safety of TwinRabTM, a combination of mAb Docaravimab and Miromavimab, in patients according to WHO guidelines for Category III suspected rabid animal bites at the end of the 35th day and Day 0 immunization.

Study Participants

A total of 200 healthy subjects (aged > 2 years) who were not previously administered anti-rabies vaccine or had no history of animal bites in the past were enrolled for the assessment of safety of the study vaccine (TwinRabTM). Eligible subjects were males and females who fell under WHO Category III exposure(s) by a suspected rabid animal < 72 hours prior to enrollment and < 24 hours if exposed to the face, neck, hand, or fingers, and treatment with the study vaccine was initiated as per the discretion of the principal investigator. Exclusion criteria for the participants included a history of any clinically significant disease (pulmonary, endocrine, autoimmune, psychiatric, cardiovascular, hepatic, or kidney) which may interfere with the study outcomes, a history of thrombocytopenia or known bleeding disorders, subjects with known major congenital defects or serious chronic illness, subjects with a history of thrombocytopenia or known bleeding disorders, and subjects who had participated in any other clinical study within the last 30 days. All subjects gave written informed consent before randomization. If the subject was a minor (aged 2-17 years), an assent form along with a Legally Authorized Representative (LAR) form had to be obtained by the subject’s parents or guardians. The subjects were free to withdraw from the study at any time without compromising their relationship with their study doctor. During the screening procedure, subject’s demographics and medical & vaccination history were checked including vital signs (blood pressure and respiratory rate) and physical examination. The eligible subjects were allocated to receive a cocktail of monoclonal anti-rabies antibody (Docaravimab & Miromavimab) on day 0 along with ARVs. ARV injections were administered by the Intradermal (ID) route, following the updated Thai Red Cross Schedule (on days 0,3,7, and 28). The vaccination was performed by trained medical site study personnel. Each subject received a single dose of 40 IU/kg body weight of TwinRabTM from the available 2.5 ml vial. TwinRabTM was infiltrated around the bite wound or wounds along with the ARV on Day 0. Routine general and systemic examination was also performed on day 0, 3, 7, and 28.

Ethical Committee Approval

The study was registered in the CTRI on 02/11/2022 with registration number CTRI/2022/11/046994 and obtained approval from the independent ethics committee of Maulana Azad Medical College and Associated Hospital, New Delhi (Ref. No.: F.1/EC/MAMC/94/06/2022/06 Dated 09th Jan 2023).

Procedure

In this study, 200 individuals with suspected rabies exposures falling under WHO category III were given a single dosage of 40 IU/kg body weight of TwinRabTM from a 2.5 ml vial. On the first visit, the ARV and TwinRabTM were infused around the bite wound or wounds. All unsolicited and solicited adverse events were thoroughly collected, recorded, and reported for the entire 35-day trial period. The severity of AEs associated with rabies treatment was assessed using the FDA Toxicity Grading Scale, and all AEs associated with the rabies vaccine were defined using the vocabulary of MedDRA Version 26.0.

Data Capturing and Statistical Analysis

An Electronic Data Capturing (EDC) system was utilized to transition patients' data from physical Case Report Forms (CRFs) to electronic CRFs. This enabled efficient and accurate data collection, storage, and management. Subsequently, statistical analysis was conducted using SAS®, Version 9.4 (SAS Institute Inc., USA). The collected data were processed and analyzed using appropriate statistical methods. Statistical analyses involved the generation of associated tables, listings, and figures to summarize and present the study's findings.

Safety Assessment

The safety of the studied vaccines was assessed by recording the Adverse Events (AEs) occurring during the study. All abnormalities found in clinical examination were noted as AEs. The solicited (injection site & systemic) AEs were recorded for 7 days post-vaccination & unsolicited (other) AEs were recorded for 35 days (+7 days) following the final dose of the PEP regimen for rabies.

Results

Overall, 200 subjects were enrolled in the study and received a single dose of 40 IU/kg body weight of World’s first Cocktail of RmABs TwinRabTM. All 200 subjects (100%) completed the study, with no exclusions or losses to follow-up among the patients (Table 1).