Preprint A phase 2a double-blind, placebo-controlled randomized trial of the SARS-CoV-2-specific monoclonal antibody AER002…, 2026, Peluso+

[SNT Gatchaman]

A phase 2a double-blind, placebo-controlled randomized trial of the SARS-CoV-2-specific monoclonal antibody AER002 in people with Long COVID

Spoiler: Authors

Michael J Peluso; Dylan Ryder; Thomas Dalhuisen; Danny Hoi Tsun Chu; Meghann C Williams; Antonio E Rodriguez; Brian LaFranchi; Joanna Vinden; Emily A Fehrman; Beatrice Huang; Rebecca Hoh; Kofi A Asare; Kathleen Bellon Pizarro; Mohammad Rahman; Emilio de Narvaez; Mark M Painter; E John Wherry; Zoe N Swank; Louise L Hansen; David R Walt; Yoshinori Fukazawa; Anisha Sekar; Steven E Bellan; Holly Tieu; Josephat Asiago; Prakash Bhuyan; Rajeev Venkayya; Robert R Flavell; Henry VanBrocklin; J Daniel Kelly; Priscilla Y Hsue; Matthew S Durstenfeld; Peter W Hunt; Leonard Calabrese; Ma Somsouk; Jeffrey N Martin; David V Glidden; Amelia N Deitchman; Timothy J Henrich; Steven G Deeks

Long COVID is a disabling chronic illness with no proven treatments. Persistence of SARS-CoV-2 has been proposed as a biological driver of the disease.

We conducted a placebo-controlled, double-blind, 2:1 randomized mechanistic trial of the SARS-CoV-2-specific monoclonal antibody AER002 in 36 participants who met the World Health Organization case definition of Long COVID. After baseline characterization, participants received a single infusion and were followed for 360 days. The primary endpoint was the PROMIS-29 Physical Health Summary Score (PHSS) at 90 days; secondary and exploratory endpoints included patient-reported and objective measures of physical, cognitive, and neurologic function as well as blood-, imaging-, and tissue-based biomarkers.

While AER002 was safe and well tolerated, no significant differences in physical health, quality of life, objective measures of physical function or cognition, or blood-based biomarkers were demonstrated between the treatment and control arms. In a post-hoc analysis, participants with a lower baseline SARS-CoV-2 antibody level and higher drug exposure were more likely to express a perceived treatment benefit based on the Patient Global Impression of Change scale (p<0.05 for anti-S, S1, and RBD).

Although AER002 was not efficacious in this proof-of-concept study of people with broadly defined Long COVID, our findings could inform recruitment or dosing strategies employed in future trials using monoclonal antibodies to target viral persistence as a driver of Long COVID.


Web | DOI | PDF | Preprint: MedRxiv | Open Access

 

[SNT Gatchaman]

Another data point against viral persistence.

I was disappointed to read this preprint, not because the result was negative, but because of what this large and ostensibly sensible and committed team then proposed to explain this result. Instead of emphasising the potential for spontaneous improvement with time (< 3 years), they offer mind-body explanations.

First the results —

we did not observe a significant improvement in functional status or overall quality of life in those receiving AER002

The PROMIS-29 Physical Health Summary Score improved in both groups between baseline and the 90-day timepoint, with no significant difference between groups

the PROMIS-29 Mental Health Summary Score (MHSS) secondary outcome improved in both groups, with no significant difference between groups.

There was also no significant difference in quality of life using the 5-Item EuroQol EQ-5D-5L Index Value Score, the 100-point Visual-Analogue Scale, or the WHODAS 2.0 Simple Score. Similar patterns in these measurements were observed at secondary timepoints (30 days, 180 days, 360 days).

Because of concerns that commonly used patient-reported outcome measurements may not adequately capture symptomatic changes in this patient population, we used the Patient Global Impression of Change (PGIC) scale to directly query participants regarding whether they perceived any clinical changes following treatment and to identify self-reported responders and non-responders. Approximately half of the participants in the treatment arm and three-quarters in the placebo arm reported a perceived response to treatment (not significant).

there was no difference in the odds of having consistent or resolving PEM between the treatment and placebo groups

At baseline, the Duke Activity Status Index (DASI42 ) total score was similar between groups, reflecting impaired functional capacity. Similarly, distance achieved on a 6-minute walk test was comparable between groups. At Day 90, there were no significant differences in either DASI or 6-minute walk test. Results were similar at secondary timepoints (30 days, 180 days, 360 days).

At Day 90 following the infusion, there were no significant differences in either ECog (Figure 3c) or CNS-Vital Signs neurocognitive index score. Results were similar at secondary timepoints (30 days, 180 days, 360 days).

At Day 90 following the infusion, there were no significant differences in either COMPASS-31 or active standing test (one positive). Results were consistent at secondary timepoints (30 days, 180 days, 360 days).

treatment was associated with modest proteomic differences relative placebo, affecting a small subset of markers linked to immune regulatory signaling and tissue remodeling processes

we did not observe any significant longitudinal differences between baseline and post-infusion [PET] images within AER002 and [placebo] groups

 

[SNT Gatchaman]

Discussion —

Participants in this trial had been experiencing Long COVID for about two years, considerably longer than the period in which SARS-CoV-2 persistence has thus far been linked to Long COVID symptoms (3-14 months). It is possible that SARS-CoV-2 persistence drives disease early on, but gives way to mechanisms like chronic immune dysfunction, autoimmunity, vascular injury, or mitochondrial dysfunction in a later post-acute phase. Longitudinal studies have suggested that the biology of ME/CFS, another multisystem disorder often attributed to an infectious trigger, could evolve over time.

It would have been good to stop there.

As in other Long COVID trials, we observed a robust response among those receiving placebo. Such findings warrant discussion, as they may inform future trial design. The placebo group exhibited higher baseline SARS-CoV-2 antibody levels than the AER002 group, which we found to be a strong predictor of improvement; this may have driven improvement in the placebo arm and blunted a therapeutic effect in the treatment arm.

Or indeed stop there. But …

It is also possible that improvements in both arms were driven by changes due to intensive observation (i.e., a Hawthorne effect), the belief that the specific intervention being studied would be beneficial (i.e., a placebo effect), or idiosyncratic improvement related to the use of concomitant medications (although participants were asked to minimize medication changes during the study).

If a placebo effect occurred, it should be noted that these responses are biologically meaningful, engaging neuroimmune networks that influence both symptom perception and inflammatory processes. Such responses can alter pain signaling, autonomic function, and inflammation. Studies in inflammatory arthritis have demonstrated that learned or expectancy-driven mechanisms can modulate disease activity and even objective inflammatory markers.

In this light, placebo responses in Long COVID trials may reflect activation of similar regulatory circuits linking the brain and the immune system. Regardless of the cause of the improvement observed in the placebo arm, it is notable that few participants reported that they had returned to their pre-COVID baseline. From a clinical standpoint, these effects highlight the profound interconnectedness of mind, brain, and body in chronic illness.

 

[Eleanor]

If a placebo effect occurred, it should be noted that these responses are biologically meaningful ...

From a clinical standpoint, these effects highlight the profound interconnectedness of mind, brain, and body in chronic illness.

"We don't know if anything happened, but it was definitely very important."