Anna Lee Petit, Kaitlin Kennedy, David Ellison, PharmD Candidates 2021 Auburn University Harrison School of Pharmacy

Companies across the United States have been focusing their efforts and resources on developing therapies to modify the outcomes of developing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19).

 Though an initial focus on treatment involved primarily repurposed drugs, research and development on novel therapeutics has moved at an almost unprecedented pace.

There is particular interest in monoclonal antibody agents to determine whether their immune suppressive effects can reduce the immediate and long-term impact of COVID-19. Monoclonal antibodies (mAbs) are engineered versions of antibodies that can be used in the treatment or prevention of infectious diseases. Antibodies are naturally produced by the immune system in response to invading viruses or other pathogens.

The theory behind monoclonal antibody use in COVID-19 is that these agents may mediate the hyperinflammatory state that patients with SARS-CoV-2 undergo, and thus help prevent both short- and long-term damage to the lungs.

There are currently 4 novel mAb agents in phase 3 for the treatment or prevention of COVID-19, which include REGN-CoV-2, lenzilumab, and ravulizumab.

 Two of these agents have been issued Emergency Use Authorizations (EUAs), but are awaiting FDA approval.

As of November 21, 2020, two SARS-CoV-2-specific mAbs, bamlanivimab and REGN-COV2, a combination of casirivimab and imdevimab, have been issued EUAs by the FDA for outpatient use in patients with COVID-19.

An EUA is authorized by the FDA to allow the use of unapproved medical products, to diagnose, treat, or prevent serious or life-threatening diseases when certain criteria are met, and there are inadequate available alternatives.

Based on an FDA review of data from a planned interim analysis of the BLAZE trial, an ongoing randomized, double-blind, placebo-controlled, phase 2 trial of bamlanivimab in 452 patients, the rate of hospitalization on day 29 was lower in the bamlanivimab group (1.6% vs 6.3% in the placebo group).

 FDA review of randomized, placebo-controlled, phase 2/3 trial to evaluate safety, tolerability, and efficacy of a single intravenous (IV) dose for treatment of COVID-19 in ambulatory adults led to its EUA.

A total of 799 patients treated with casirivimab/imdevimab reduced COVID-19-related medical visits by 57% through day 29 compared with placebo.

 Both bamlanivimab and casirivimab/imdevimab were studied in adults and adolescents 12 years and older weighing 40 kilograms or more with mild or moderate COVID-19 at high risk for progressing to severe COVID-19 and/or hospitalization, and outpatient use only.

The EUAs were subsequently approved in this patient population, and are to be administered as IV infusions.

 Bamlanivimab is administered as a single IV infusion of 700 mg over 60 minutes.

Casirivimab/imdevimab is administered as a single IV infusion that consists of 1200 mg of casirivimab and 1200 mg of imdevimab.

 Both bamlanivimab and casirivimab/imdevimab should be administered as soon as possible after positive viral test for SARS-CoV-2 and within 10 days of symptom onset.

Lenzilumab is being studied to neutralize granulocyte-macrophage colony-stimulating factor in hopes to shorten hospital length and improve oxygenation in patients diagnosed with COVID- 19 pneumonia.

 Lenzilumab was approved to be studied as an emergency single-use investigational new drug in a prospective case cohort study of 12 participants compared with a control group of 27 untreated patients.

It was studied at a treatment dose of 600 mg IV given over 1 hour every 8 hours for 3 doses.

 The primary end-point tested time to clinical improvement as defined as the observation of a 2 point or higher change in the designated 8-point clinical endpoint scale. Lenzilumab showed a significant improvement in this endpoint with a median of 5 days to clinical improvement compared with a median of 11 days in the untreated cohort (P=0.006).

Lenzilumab significantly decreased median hospital length of stay vs control (5 days vs. 11 days) (P=0.006) and significantly improved oxygenation compared with the untreated cohort when observing patients free of acute respiratory distress syndrome (ARDS) (p<0.001). Other data lend to the idea that lenzilumab improves ventilator-free survival, but did not reach significance in this trial.

Lenzilumab also may have a positive impact on reducing the inflammatory response triggered in some patients with COVID-19. It significantly reduced inflammatory biomarkers including CRP and IL-6 from baseline to day 4.

Lenzilumab was well-tolerated in all patients with no observed treatment-related adverse events. The data from the case study have inspired a phase 3, randomized, placebo-controlled study to verify and expand on these findings.

This study started in April 2020 with 300 participants and was designed with specific outcomes to define its role in therapy in addition to remdesivir and dexamethasone for COVID-19.

 Results of this study have not yet been disseminated.

Ravulizumab, also known as Ultomiris, is currently in a phase 3 trial to evaluate the mortality of patients after 29 days who have severe pneumonia due to COVID-19, acute lung injury, acute respiratory distress syndrome, or viral pneumonia.

 This open-label, randomized, controlled trial has 270 patients enrolled, with a 2:1 ratio of patients receiving ravulizumab with supportive care compared to receiving supportive care alone.

The weight-based doses of IV ravulizumab will be administered to patients 18 years or older who meet criteria on days 1, 5, 10, and 15. Inclusion criteria included patients who had confirmed COVID-19 and required hospitalization. 

Furthermore, patients also had to have severe pneumonia, an acute lung injury, or acute respiratory distress syndrome, and the patients had to be mechanically vented. For patients who are 40 kg or greater to less than 60 kg, a 2400 mg dose is used. For patients 60 kg or greater to less than 100 kg, a dose of 2700 mg is used. Finally, for patients greater than or equal to 100 kg, the dose of 3000 mg is to be used.

Depending on the weight of the patient, the day 1 doses were dependent solely on weight; however, patients on days 5 and 10 in the protocol were to receive additional 600 mg (40 kg-60 kg) or 900 mg (60 kg or greater).

 Finally, day 15 was a set dose for all patients with 900 mg being administered.

 Recruitment for this trial started on May 11, 2020, with hopes of recruitment to be finished by November 30, 2020.

In conclusion, SARS-CoV-2 mAbs have shown to be promising pharmacotherapy options for COVID-19 in their phase 3 clinical trials. Looking into the future, with further investigation of these specific therapies, we can hope to better understand the mechanisms behind treating COVID-19 as well as the long-term impact of the therapies on the patients themselves.

With the EUA approved for casirivimab/imdevimab for outpatient use, with more data from the phase 3 trial, there is hope it will receive FDA approval. The data with lenzilumab have set high expectations for EUA consideration or FDA approval, but whether that will occur based on what information is available remains to be determined.

We are expectantly awaiting the results of the ultomiris trial to hypothesis its place in treatment. The completion of these phase 3 trials will help solidify the FDA’s recommendation on their role in the treatment against SARS-CoV-2. 

There is hope that all of these therapies will contribute to improved outcomes when treating COVID-19 as we continue to become more confident and successful in managing this novel pathogen.

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Articles

There is particular interest in monoclonal antibody agents to determine whether their immune suppressive effects can reduce the immediate and long-term impact of COVID-19.