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Fall 2021 - Innovation

Anti-COVID Monoclonal Cocktails

Newly created treatments for high-risk COVID-19 patients have proved highly effective. Unfortunately, challenges with their distribution and administration have limited their use.

As attention fixates on the development of vaccines against COVID-19, researchers have achieved another equally impressive yet less-celebrated victory: the creation of antiviral monoclonal cocktails. The concept of discovering and cloning antibodies against deadly viruses has been around for decades, but it only came to fruition during this pandemic. With Regeneron’s casivirumab/indevimab cocktail and Lilly’s bamlanivimab and recently approved etesevimab, there is now a range of precision medicine-targeted therapies against COVID-19. The speed of their development was nothing short of miraculous, and while efficacy/safety data are still limited to a handful of studies, observations thus far have convinced the U.S. Food and Drug Administration (FDA) to grant them emergency use authorization (EUA). Yet, while their development was an amazing example of the tremendous possibilities of collaboration between the public and private sectors, their distribution and administration have been met with myriad challenges.   

All of these monoclonal antibodies are designed to neutralize the receptor binding domain of the spike protein of SARS-CoV-2 (the virus that causes COVID-19) to prevent it from binding onto the ACE2 receptor and enter the host cell. They were derived from evaluation of convalescent blood from recovered patients. Of all of the targeted antibodies produced by the B cells directed against SARS-CoV-2, the key was to find the ones with the best ability to bind to the spike protein to specifically target the virus’s ability to infect the cell. State-of-the-art sequencing, bioinformatics and manufacturing technologies allowed for rapid identification, selection and production to initiate clinical studies. These monoclonal combinations target different regions of the receptor-binding domain and do not compete with each other for binding. By using more than one monoclonal to neutralize the spike protein, the chance of evolution of viral variants/mutations that could potentially elude neutralization in the future is decreased. In preclinical animal model studies, all of the monoclonals demonstrated efficacy in neutralizing the virus to significantly decrease replication and viral load in the host. 

Both Regeneron and Lilly monoclonal cocktails have similar eligibility criteria based on the EUA. They were created to treat ambulatory adolescent and adult patients who have mild-to-moderate COVID-19 and are at a high risk for hospitalization and serious complications but have not yet needed to be hospitalized. High risk is defined the same for both of the EUAs: over 65 years of age, immunocompromised state (either immunodeficiency or on immunosuppressive therapies), diabetes, chronic kidney disease or obese with a body mass index (BMI) greater than 35. Patients over 55 years of age may be eligible if they also have hypertension, chronic obstructive pulmonary disease or other forms of chronic lung disease or heart disease. For adolescents to be eligible, they must be either overweight with a BMI greater than the 85th percentile for age/gender, have heart disease, chronic respiratory disease (i.e., asthma), be dependent on a medical technology or device, have sickle cell disorder or have a developmental neurologic disorder. However, the complexity surrounding the full understanding of these eligibility criteria may be a challenge in the broad adoption of these therapies.  

Lilly Monoclonals: Bamlanivimab and Etesevimab

The Lilly monoclonals have undergone a series of clinical trials, including the pivotal study BLAZE-1 in the ambulatory population that generated data for FDA to grant the EUA, as well as studies looking at lower-dose combinations, larger population sizes and postexposure prophylaxis. Because the study in hospitalized patients was stopped due to lack of efficacy, the therapies are indicated only for ambulatory use. 

Initially, FDA approved the bamlanivimab monotherapy because it demonstrated significant efficacy and appeared to be safe and tolerable. However, FDA recently discontinued the EUA for bamlanivimab monotherapy due to the concern of developing treatment-emergent viral variants. The treatment-emergent variant rate for their placebo arm was 4.8 percent, but the rate for the bamlanivimab monotherapy was 9.4 percent. On the other hand, the treatment-emergent variant rate for the combination therapy group was only 1 percent, which was substantially lower than the placebo group. Therefore, this highlights the fact that combination therapy, which blocks multiple targets on the receptor-binding domain of the spike protein, decreases the likelihood of viral mutations. 

The current EUA approval is for combination therapy of bamlanivimab 700 mg plus etesevimab 1,400 mg mixed together as an intravenous (IV) infusion given over at least one hour. This is based on efficacy and safety data from the combination therapy clinical trial. And, while the clinical trial used a higher dose of both monoclonals, it was determined a lower dose of each could achieve similar antiviral activity as the higher-dose formulation. Based on publicly available data, the safety and tolerability did not raise any significant concerns in the clinical trials. Treatment-emergent adverse events were not significantly different between the combination monoclonal group versus the bamlanivimab monotherapy or the placebo group. Adverse events were also determined to be mostly mild or moderate, although there was a case of anaphylaxis that resolved with epinephrine treatment. In the studies, around 1 percent to 2 percent of subjects who received the monoclonals developed some mild to moderate immediate hypersensitivity events that all resolved. 

From an efficacy standpoint, the combination therapy group demonstrated a significant decrease in viral load compared to placebo from day three to day 11 post-administration. Patients with persistently higher viral load had worse clinical outcomes, and the percentage of those patients was much lower in the combination therapy group compared to the bamlanivimab monotherapy group or the placebo group. Clinical outcome measures also demonstrated efficacy. By the end of the 11 days of observation, the symptom score reduction was over eight points compared to placebo, and was statistically significant. The rate of hospitalization/emergency department (ED) visits for 28 days after therapy was 0.9 percent for the combination monoclonal group compared to 1.6 percent in the bamlanivimab monotherapy group and 5.8 percent in the placebo group. That is an 84 percent relative rate reduction in the hospitalization/ED visit rate when comparing the combination therapy versus placebo. Specifically, when the high-risk group of patients who were either older than 65 years or obese with a BMI greater than 35 was evaluated, reductions in hospitalization/ED visits was even more staggering: 0 percent in the combination monoclonal group and 13.5 percent in the placebo group. 

Regarding efficacy of neutralization of newly emerging viral variants, the FDA fact sheet on the EUA states the bamlanivimab and etesevimab combination therapy had no reduction in activity against the United Kingdom variant, but did demonstrate varying degrees of reduced ability to neutralize the South African, Brazil, California and New York variants.

Regeneron Monoclonals: Casirivimab and Imdevimab

The Regeneron monoclonals are approved for combination IV infusion therapy at 1,200 mg for each of the monoclonals (total 2,400 mg) administered over at least one hour. Multiple clinical trials were conducted, and more ongoing studies are evaluating the safety and efficacy of this combination therapy. The current EUA indication is for treatment of nonhospitalized high-risk patients, but additional studies are underway exploring its potential use for hospitalized patients, household contact prophylaxis and subcutaneous formulations. As of the end of January 2021, more than 12,000 patients have been enrolled in clinical trials for these therapies.  

Combination therapy was able to significantly reduce the viral load compared to placebo at both the lower dose (approved total combination therapy of 2,400 mg) and higher dose (8,000 mg) with a similar degree of viral load reduction. Clinical outcome measures showed the combination monoclonal therapy group was able to reduce medically attended visits (combined number of ED visits, hospitalizations, urgent care visits, physician office visits and telemedicine visits) by 57 percent compared to placebo (from 6.5 percent in the placebo group to 2.8 percent in the 2,400 mg dose group). Looking only at ED visits or hospitalizations 28 days post-treatment, the rate was 4 percent for the placebo group and 2 percent for the 2,400 mg treatment group. 

Overall, the combination therapy was well-tolerated, and there did not appear to be any significant safety concerns. The serious adverse event rate was 1.6 percent in the 2,400 mg treatment group and 2.3 percent in the placebo group, and none of these events was determined by investigators to be related to treatment. The high-dose (not approved dose) group had a 1.5 percent rate of infusion reactions compared to 0.4 percent in the placebo arm, but the 2,400 mg dose group (approved dose) had no observed infusion-related reactions reported in the study. There was one anaphylactic reaction following infusion of the combination therapy that resolved with epinephrine use. 

The ability of casirivimab and imdevimab combination therapy to neutralize newly emergent variants was examined as well, and according to the FDA fact sheet, there was no significant reduction in neutralization activity against any of the characterized variants studied.  

Challenges with Adoption

The hope for the development of these monoclonal therapies was that they would be widely distributed and utilized to prevent serious morbidity and mortality in symptomatic high-risk patients. However, while the government has been eager to fund the development, production and distribution of these therapies, the actual uptake has been underwhelming and slow due to a number of reasons. 

First, since they are approved under the EUA and do not have full FDA approval, the manufacturers are not permitted to market them to clinicians or patients, which reduces the overall awareness of their existence. Many physicians today are either uninformed or underinformed about the availability and efficacy/safety data on these therapies. A significant number of patients are also unaware of their existence. Even among patients who are aware of their existence, some believe they are difficult to obtain or available only to privileged groups. 

Second, since these therapies are authorized only for nonhospitalized ambulatory patients, many of the typical COVID-19 frontline clinicians (hospitalists, ED physicians, pulmonologists and infectious disease specialists) who are predominantly hospital-based are not as significantly involved in the process of identifying eligible candidates and administering therapy. The EUA for these monoclonals shifts the focus to the community ambulatory providers such as primary care physicians who do not typically prescribe biologic therapies that require IV infusions. Many primary care providers are heavily reliant on telemedicine during the pandemic, and it may be difficult to assess degree of symptoms without physical exam or vitals to determine eligibility for the treatments. 

Third, biologic therapies are usually distributed via specialty pharmacies or administered in infusion centers. But due to the pandemic, many infusion centers have limited capacity and may not allow patients with active infections to enter due to risk of potential spread of infection to others. Special infusion centers had to be created specifically for the administration of these therapies with areas for monitoring after infusion. 

Furthermore, healthcare is far more conservative than other technological fields, and adoption of change is much slower. Professional organizations, academic societies and specialist associations often take years to adopt new guidelines or incorporate new data into existing guidelines. What’s more, the general adage of medicine is to do no harm, and many academics and specialists feel they still need larger study populations and longer observation periods to fully endorse novel therapy regimens. 

There are multiple ways to overcome these challenges to help bring these lifesaving therapies to at-risk patients faster. For example, the government at all levels should increase the awareness campaign regarding the availability of these therapies. A significant amount of attention has been given to the vaccine rollout, but on state, local and federal government health-related agencies’ websites, there should also be information regarding the monoclonal therapies. More attention should be placed on outpatient specialty societies that focus on respiratory disease and are comfortable with biologic therapies such as allergists/immunologists and ambulatory specialists who can evaluate for eligibility and potentially prescribe treatment. Networks of providers should be developed to facilitate the multidisciplinary care of COVID-19 patients before they reach the hospital. Lastly, more treatment centers should be established, and their locations should be publicized so all ambulatory providers in the region know where they can send their patients. A concerted collaborative effort of clinicians, hospitals, infusion centers and medical societies will help raise awareness and lead to better outcomes for these patients.

References

1. U.S. Food and Drug Administration. Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of Bamlanivimab and Etesevimab and Full EUA Prescribing Information. Accessed at www.fda.gov/media/145802/download.

2. U.S. Food and Drug Administration. Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of Regen-Cov (Casirivimab and Imdevimab) and Full EUA Prescribing Information. Accessed at  www.fda.gov/media/145611/download.

3. Skovronsky DM. SARS-CoV-2 Neutralizing Antibodies for Treatment of COVID-19. Presentation at FOCIS, October 2020.

Bob Geng, MD, MA
Bob Geng, MD, MA, studied medicine at Washington University School of Medicine in St. Louis, where he also completed his residency training in internal medicine. He is currently an assistant professor in allergy and immunology at the University of California, San Diego. Dr. Geng received his bachelor’s and Master of Arts degrees in Georgetown University’s School of Foreign Service.