Did Black Patients With COVID-19 See Greater Benefits With Novel Mab Therapy?

Hospitalized Black/African-American patients with COVID-19, and a baseline C-reactive protein (CRP) <150 mg/L, experienced a "markedly greater improvement" in survival without ventilation (SWOV), according to an analysis of LIVE-AIR study data.

While SWOV at 28 days was improved among all patients with the agent versus placebo (hazard ratio 2.54, 95% CI 1.46-4.41, P=0.0009), the benefit was particularly pronounced among the subset of Blacks/African Americans patients (HR 8.9, 95% CI 1.08-73.09, P=0.0418), reported Charles Burger, MD, of the Mayo Clinic in Jacksonville, Florida, at the Society of Critical Care Medicine (SCCM) virtual Critical Care Congress.

Lenzilumab is a granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralising monoclonal antibody (Mab) whose developer, Humanigen, failed to garner an FDA emergency use authorization (EUA) in September 2021. LIVE-AIR results, published in the March 2022 Lancet Respiratory Medicine, brought better news, showing that lenzilumab significantly improved SWOV in hospitalized patients with COVID-19, with a safety profile on par with placebo.

In the current analysis, "The effect is quite significant and supports further study in the Black/African-American population," Burger told MedPage Today, although he declined to speculate why the effect may be so strong in these patients. In LIVE-AIR, 14.8% of the >500 patients were Black/African-American.

In the SCCM abstract, Burger's group explained that "Black/African Americans (B/AA) are twice as likely as Whites to develop COVID-19, possibly due to disparities in healthcare access and genetics. Mutations in the angiotensin converting enzyme gene enabling greater SARS-CoV-2 replication may be overexpressed in B/AAs leading to increased viral load, morbidity, hospitalizations, and mortality."

Hyun Ah Yoon, MD, of Albert Einstein School of Medicine in New York City, called the findings "interesting" and "hypothesis-generating," but cautioned that "it is an exploratory analysis with a small sample size, and wide confidence intervals suggesting that there is an uncertainty with the estimate."

Yoon, who was not involved in LIVE-AIR, pointed out to MedPage Today that the data do not "provide precise representation of the effect in the population. It is difficult to say that it is a real effect, and it needs to be validated in a larger sample size."

She theorized that, if the effect is real, African-American patients may be younger "due to difficulty with early access to healthcare or higher comorbid conditions such as hypertension, diabetes, or obesity. In general, we see fewer younger individuals hospitalized unless they are very sick."

But there is a significant need in general for new Mab treatments for COVID-19, Yoon stated. Interleukin-6 (IL-6) receptor-blocking Mabs, such as tocilizumab (Actemra) or sarilumab (Kevzara), are used with corticosteroids in critically ill patients with poor prognoses, she said, and the JAK 1/2 inhibitor baricitinib (Olumiant) is recommended for patients who can't tolerate corticosteroids.

"There is a gap in treatment options that can halt the disease progression between the early viral replicatory and hyperinflammatory phase. We need better treatment options to prevent patients progressing to meet the criteria for IL-6 inhibitors," she said.

Yoon said LIVE-AIR results are promising as the "trial suggests that lenzilumab may have a role in patients requiring low-flow oxygen, which is a stage earlier than when we typically use the IL-6 inhibitors. This makes sense as GM-CSF is a more upstream target in the inflammatory cascade, and control of it may theoretically allow better and earlier control of cytokine storms."

"The findings may...have important clinical implications, especially now in the vaccine era when patients may come in with milder disease and/or individual awareness of COVID-19 has heightened, and may seek care earlier if infected, which will give the clinicians the opportunity for earlier intervention," she noted, adding that another subgroup analysis by LIVE-AIR investigators found that patients ages <65 had a better response to lenzilumab.

"It could be that hyper-inflammation drives the pathology more in younger individuals, who require hospitalization, as opposed to older individuals who may have more of an issue clearing the virus, and immunosuppressive agents may actually be harmful," Yoon stated.

Burger's group also found that the likelihood of SWOV was significantly improved by lenzilumab in all patients with baseline CRP <150 mg/L and ages <85 (HR 3.04, 95% CI 1.68-5.51, P=0.0003).

Serious adverse events (AEs) overall were similar across treatment groups, with 26.7% of patients in the lenzilumab group and 32.7% in the placebo group experienced grade ≥3 AEs, according to the LIVE-AIR investigators.

In January 2022, Humanigen announced that the phase II/III ACTIV-5/BET-B study achieved its target enrollment. The estimated study completion date is October 2022, and Cameron Durrant, Humanigen chair and CEO, said in a press release "We have alignment with the FDA that, if the trial is successful, we can include the results from ACTIV-5/BET-B in an amended [EUA] submission for lenzilumab for hospitalized patients with COVID-19."