Antibody Ambivalence: Why the Constraints on Monoclonal Antibodies in COVID-19
Despite an average vaccination rate of 1.41 million doses per day in the U.S, the pandemic continues to take its toll on the population. In our last post, my colleague wrote of his relative who unfortunately contracted coronavirus. However, we are pleased to inform that she received a monoclonal antibodies treatment, and is currently recovering.
Today, I tell my own personal story of a friend who is currently fighting COVID-19 and thought he could access this treatment as he was well aware of their significant benefits. After hours on the phone with multiple sites with no avail, he felt that his only choice was to drive to the emergency room. Once there, he described a harrowing experience of trying to make his case for treatment with exhausted physicians and other staff members. To make matters worse, he encountered a family member who exclaimed “oh god why now?” during their loved one’s final moments. After all of this, since our friend is in his forties and lacking any of the risk factors which might define him eligible per the FDA emergency use authorization (EUA), he was denied treatment.
Today’s post discusses why patients who are symptomatic yet not high risk, are unable to access monoclonal antibodies. Although these therapies have been made available through EUA, they are reserved for patients considered high risk, such as aged 65 and older with the general U.S. population deemed ineligible at this time. The fact that there are numerous cases where individuals who do not meet the high risk criteria have died begs the question of why the EUA stipulations for monoclonal antibodies are particularly narrow. If these treatments can save lives, why are healthcare providers (HCPs) not allowed to administer them to a broader population?
Emergency Use Authorization for Monoclonal Antibodies
On November 9th, 2020, the FDA granted EUA to Eli Lilly’s monoclonal antibody therapy, bamlanivimab for use in COVID-19. Regeneron’s authorization soon followed with the FDA granting EUA to casirivimab and imdevimab. Both EUAs stated that the treatments are for people “who are at a high risk for progressing to severe COVID-19.” While the availability of this treatment should be encouraging news, this designation led to headaches for Health Care Providers (HCPs) as it in fact, forces them into a tough situation. There are very specific criteria for who is defined as “high risk, which is related to factors including age and comorbidities. However, HCPs continue to see patients who don’t meet this risk profile yet go on to have severe symptoms or even succumb to the disease. While there are likely patients who are not considered high risk and could benefit from this treatment, they will not receive monoclonal antibodies in the short-term under the current regulatory framework.
The Clinical Trial
The reason for the current regulatory framework lies in the data from the clinical trial which informed the EUA. Pressed for time, needing to supply a treatment for a deadly disease, Eli Lilly conducted a clinical trial for its monoclonal antibody treatment. In terms of enrollment, 70% of patients fit the criteria of high risk, similar to that being used in the current EUA. The enrollment data makes sense as the overwhelming majority of coronavirus deaths are attributable to individuals with comorbidities or are over 65.
As far as results, the trial’s endpoints focused on viral load (primary) and hospitalizations (secondary). In terms of viral load, the researchers observed that there was little difference between the patients and placebo group as viral loads in both groups decreased. While there was a decrease in the overall rate of hospitalizations with the monoclonal antibody compared with placebo, a post hoc analysis noted an amplified effect in those who were considered high risk.
To quote the New England Journal of Medicine, “In a post hoc analysis examining hospitalization among patients who were 65 years of age or older and among those with a BMI of 35 or more, the percentage who were hospitalized was 4% (4 of 95) in the LY-CoV555 group and 15% (7 of 48) in the placebo group. Only 1 patient in the trial (in the placebo group) was admitted to an intensive care unit.”
What all of this data boils down to is that due to the limited nature of the data (Eli Lilly’s EUA was based on an interim analysis), the FDA only felt confident enough to approve the treatment for those in high risk populations as that is what the data supports. The FDA needs more data to grant full approval. Only at that point, HCPs will be able to administer the treatment off-label to non-high risk populations.
Returning to the opening question of why our friend could not receive treatment, simply, there is not enough data to support monoclonal antibodies as treatment for non-high risk patients. Thus, the FDA, using an EUA, limited the scope of the treatment to only populations the data supported.
While anecdotally the merits of monoclonal antibodies are significant, scientifically that data remains limited. As of this writing, Eli Lilly, NIAID, and AIDS Clinical Trials Group are currently working on a trial of this treatment in non-high risk patients. With the conclusion of that trial, it is possible that we might see full approval of monoclonal antibodies, pending, of course, positive results.
Melissa Hammond, MSN is Managing Director at Snowfish.