Phase 2 study evaluates safety and efficacy of asunercept in COVID-19 patients

By Vijay Kumar MalesuReviewed by Lily Ramsey, LLMNov 18 2024

While the trial confirmed asunercept’s safety and tolerability, it failed to achieve statistically significant improvement in clinical outcomes compared to standard care.

Study: Efficacy and safety of asunercept, a CD95L-selective inhibitor, in hospitalised patients with moderate-to-severe COVID-19: ASUNCTIS, a multicentre, randomised, open-label, controlled, phase 2 trial. Image Credit: Pormezz/Shutterstock.com

In a recent study published in the eClinicalMedicine, a group of researchers evaluated the efficacy and safety of asunercept, a CD95 ligand (CD95L)-binding protein, in hospitalized patients with moderate-to-severe coronavirus disease 2019 (COVID-19) to determine its potential clinical benefit in improving patient outcomes.

Background

COVID-19 has infected over 775 million people and caused over 7 million deaths globally as of March 2024. While most cases are mild, severe complications like pneumonia, respiratory failure, and acute respiratory distress syndrome (ARDS) occur in vulnerable populations, leading to high intensive care unit (ICU) mortality rates.

Emerging variants with increased transmissibility or immune escape further compound the challenge. CD95L is implicated in lung injury and immune dysregulation, contributing to ARDS and poor prognosis.

Preclinical studies suggest that blocking CD95L can reduce lung failure and improve survival in viral infections. Further research is needed to validate its therapeutic potential in humans.

About the study

Asunercept in COVID-19 Treatment Investigative Study (ASUNCTIS) trial was conducted at 12 sites across Europe. Eligible participants had laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or typical radiological findings consistent with viral pneumonia.

The study adhered to ethical standards, including the Declaration of Helsinki and relevant local regulations, with written informed consent obtained from all participants or their legal representatives.

Patients were randomly assigned to receive standard of care (SOC) alone or SOC plus one of three weekly intravenous doses of asunercept (25 mg, 100 mg, or 400 mg).

The primary endpoint was the time to sustained clinical improvement on the World Health Organization (WHO) clinical severity scale over two consecutive days within 29 days of randomization.

Secondary endpoints included measures of oxygenation, ventilation, ICU admission, hospitalization duration, and mortality. Safety was assessed through adverse events (AEs), vital signs, laboratory findings, and immunological markers.

Randomization was stratified by respiratory support level, with a competitive enrollment strategy and unmasked study assignments. Statistical analysis focused on time-to-event outcomes using Kaplan–Meier plots and Cox regression models.

Results were analyzed in modified intent-to-treat and per-protocol populations, with exploratory analyses conducted for lymphocyte recovery and subgroup effects. The trial was monitored by an independent Data Safety Monitoring Board (DSMB) to ensure safety and protocol adherence.

Study results

Between October 9, 2020, and September 24, 2021, 440 patients were screened for eligibility, with 438 ultimately randomized across sites in Spain and Russia. Participants were allocated into four groups: 110 received SOC alone, while 109, 109, and 110 patients received SOC plus asunercept at doses of 25 mg, 100 mg, or 400 mg, respectively.

Of these, 350 patients completed the study or recovered fully before the end of therapy, while 88 discontinued prematurely due to death, investigator decision, AEs, or other reasons. Only one participant was vaccinated during the trial, as vaccines were not widely available.

Baseline characteristics showed slight imbalances, particularly in comorbidity profiles. The primary endpoint, defined as sustained clinical improvement of at least one category on the WHO clinical severity scale, was achieved by 59.1% of patients in the modified intent-to-treat (mITT) population.

Improvements were observed more frequently in the asunercept groups (61–63%) than in the SOC group (51%). Median time to clinical improvement was shorter in all asunercept arms (8-9 days) compared with SOC (13 days), confirmed by Kaplan–Meier analysis and Cox regression models.

Post hoc analyses revealed faster recovery in patients treated with asunercept, with the combined asunercept group showing a median improvement time of 8 days versus 13 days in SOC.

Subgroup analyses for WHO category four patients demonstrated that clinical improvement occurred in more patients in the asunercept arms (60–61%) compared to SOC (47.1%), with shorter times to improvement. Sensitivity analyses reinforced these findings, showing consistent trends toward faster recovery across the asunercept groups.

Secondary endpoints, including oxygenation, hospitalization duration, ventilation, ICU admission, and mortality, showed no significant differences between groups. However, a dose-dependent effect on lymphocyte recovery was noted in the asunercept 100 mg and 400 mg groups, supported by pharmacokinetic and modeling analyses indicating asunercept's impact on lymphocyte regeneration.

Safety analyses revealed comparable rates of AEs and serious adverse events (SAEs) across all groups. Among 290 recorded AEs, only two were deemed possibly related to asunercept, involving a Klebsiella infection and acute kidney failure. Laboratory parameters showed no clinically significant changes.

Conclusions

To summarize, asunercept showed a favorable safety profile with few mild or moderate adverse events. Although the primary endpoint was not statistically significant, trends indicated faster clinical improvement, particularly with the 100 mg dose, reducing time to recovery by 4-5 days compared to standard care.

Post-hoc analyses confirmed this trend across combined dose groups. Asunercept showed no increased risk of super-infections or compromised SARS-CoV-2 clearance and may reduce lymphocytopenia via reduced CD95L-mediated T-cell apoptosis.