{'fraction_non_alphanumeric': 0.03404307997028968, 'fraction_numerical': 0.023892052488239664, 'mean_word_length': 5.134396355353076, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
REGN-EB3: First Approval

REGN-EB3 (INMAZEB®, Regeneron Pharmaceuticals) is a combination of three fully-human monoclonal antibodies—atoltivimab (REGN3470), maftivimab (REGN3479), and odesivimab (REGN3471) —that target Ebola virus glycoprotein. Based on the results of the PALM study conducted during an Ebola outbreak in the Democratic Republic of Congo, REGN-EB3 was recently approved by the US FDA as a treatment for Ebola virus infection. This article summarizes the milestones in the development of REGN-EB3 leading to this first approval for the treatment of infection caused by Zaire ebolavirus (Ebola virus) in adult and paediatric patients.

REGN-EB3 received its first approval on 14 October 2020 in the USA for the treatment of infection caused by Zaire ebolavirus in adult and paediatric patients [2,3]. The recommended dosage is 50 mg/kg of atoltivimab, 50 mg/ kg of maftivimab, and 50 mg/kg of odesivimab diluted and administered as a single IV infusion [3].

Company Agreements
In September 2015, Regeneron entered into an agreement with the Biomedical Advanced Research and Development Authority (BARDA) of the US Department of Health and Human Services (HHS) to develop, test and manufacture a monoclonal antibody therapy for the treatment of Ebola virus infection. Under the terms of the agreement HHS provided ≈ $US17 million for preclinical development and antibody manufacturing intended to support an investigational new drug application (NDA) to the US FDA. The agreement included an option for an additional $21 million to fund a phase I study in volunteers and further manufacturing and development studies [4].
In October 2017 HHS further agreed to provide ≈ $US17 million in initial committed funding for development of REGN-EB3 with subsequent phases of funding earmarked to support clinical development, a potential biologics licensing application (BLA) and initial procurement of the therapy for the US Strategic National Stockpile [5].
In July 2020 BARDA entered into an agreement to procure REGN-EB3 from Regeneron in keeping with the HHS goal of building national preparedness for public health emergencies. Regeneron expects to deliver an established number of treatment doses over the course of six years and anticipates payments of ≈ $10 million in 2021 and an average of $67 million per year between 2022 and 2026 [6].

Pharmacodynamics
Using surface plasma resonance (SPR) atoltivimab, odesivimab and maftivimab had K D values of 7.74, 8.42 and 2.97 × 10 -9 mol/L, respectively, for recombinant histidinetagged Makona strain Ebola virus glycoprotein ectodomain protein, indicative of high-affinity binding. Only odesivimab demonstrated specific binding to soluble virus glycoprotein, indicating that it binds within the first 295 amino acids of the common region of Ebola virus glycoprotein and soluble virus glycoprotein [1].
Atoltivimab, maftivimab and odesivimab did not compete for binding to Ebola virus glycoprotein when assessed using the Octet HTX system, and were shown to bind simultaneously to Ebola virus glycoprotein in a three-step sequentialbinding study performed using SPR. Single-particle, negative-stain electron microscopy indicated that each antibody binds to a different site on the glycoprotein molecule [1].
In the rhesus macaque model of Ebola virus infection three doses of the atoltivimab, odesivimab and maftivimab cocktail on days five, 8 and 11 post-infection (50 mg/kg total antibody per dose) provided complete protection from lethal disease, with placebo-treated animals succumbing by day 9 post-infection. In a similar study, a single 150 mg/kg dose of atoltivimab, odesivimab and maftivimab produced a similar result to that observed with the three 50 mg/kg dose regimen. In a third study in rhesus macaques designed to evaluate the minimal effective single dose of the atoltivimab, odesivimab and maftivimab cocktail 100 mg/kg was the lowest dose tested that gave best control of symptoms [1].

Pharmacokinetics
The pharmacokinetic profiles of atoltivimab, odesivimab and maftivimab have been studied in a double-blind phase I dose-escalation study in volunteers. Volunteers were randomized to receive 3 mg/kg (n = 3), 15 mg/kg (n = 3), 60 mg/kg (n = 6) and 150 mg/kg (n = 6) doses of atoltivimab, odesivimab and maftivimab (administered together as a single IV infusion), or placebo (n = 6). Changes in serum concentration over time were biphasic for all three monoclonal antibodies, comprising an initial rapid distribution phase and a slow elimination phase. All three antibodies had a linear, dose-proportional pharmacokinetic profile, with similar dose-normalised maximum concentrations and AUC 0-inf across all four dose groups, and dose-independent overall mean t ½ values (27·3, 21.7 and 23.3 days for odesivimab, atoltivimab and maftivimab, respectively) [7].   [8]. The trial was originally designed as a three arm study evaluating the efficacy of ZMapp, remdesivir and Mab114; however, the protocol was subsequently updated to include a REGN-EB3 arm, with data from this group compared only with those from patients in the ZMapp group enrolled on or after the time the REGN-EB3 group was added. Only data from this comparison are described below. Despite the extraordinary challenges encountered in conducting the trial (e.g. regional violence, unstable electrical power grid, transportation difficulties, history of high morbidity from other infectious diseases), a successful conclusion was achieved through careful planning, cooperation, support, and coordination from multiple organisations and support staff [8].
Patients were randomized to treatment with REGN-EB3 150 mg/kg as a single infusion on day 1 (n = 155) or IV ZMapp 50 mg/kg every third day beginning on day one for a total of three doses (n = 154). All patients also received standard care, comprising IV fluids, daily clinical laboratory testing, correction of hypoglycaemia and electrolyte imbalances, and administration of broad-spectrum antibiotic and antimalarial drugs [8].
The mortality rate at 28 days (primary endpoint) was 17.8% lower in the REGN-EB3 group than in the ZMapp group (95% confidence interval, − 28.9 to − 2.9; p = 0.002). The survival benefit observed in REGN-EB3 recipients was also evident in sensitivity analyses adjusted for potential baseline imbalances including duration of symptoms, nucleoprotein cycle threshold (Ct) value, patient age, creatinine level, alanine and aspartate aminotransferase levels, and patient reported vaccination. The median time to the first negative result on RT-PCR assay for Ebola virus nucleoprotein was 15 days in REGN-EB3 recipients compared to 27 days in the ZMapp group (secondary endpoint). For the purposes of this analysis patients who had died were considered as not having had viral clearance [8].
No immunogenic responses to atoltivimab, maftivimab or odesivimab were detected at baseline or through to 168 days post-dose in any subjects participating in the phase I dose escalation trial described above [7].

Ongoing Clinical Trials
An expanded access protocol for emergency use of REGN-EB3 is available for individuals in an Ebola endemic region with documented positive polymerase chain reaction for Ebola virus infection who are symptomatic (NCT03576690).

Current Status
REGN-EB3 received its first approval on 14 October 2020 for the treatment of Zaire ebolavirus (Ebola virus) infection in adult and paediatric patients in the USA [2].

Declarations
Funding The preparation of this review was not supported by any external funding.

Conflict of interest
Changes resulting from any comments received during the peer review process were made by the authors on the basis of scientific completeness and accuracy. A. Markham is a contracted employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content.
Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability Not applicable.