This randomized, placebo-controlled phase 2 trial assessed the efficacy and safety of YKYY017, an inhaled aerosolized membrane fusion inhibitor, for the treatment of COVID-19. Most enrolled patients had mild COVID-19 disease. The primary outcome of the phase 2 trial was not met. Although inhaled 20 mg YKYY017 demonstrated a signal for higher viral load reduction on Day 4, neither 20 mg or 10 mg YKYY017 showed significant difference from placebo. 20 mg YKYY017 group might have approximately 1-day shorter time to sustained symptom recovery and time to sustained symptom alleviation. The adverse events were mostly mild to moderate.

Although YKYY017 did not achieve significant differences from placebo at any measured time point versus placebo for the viral load reduction outcome, the potential antiviral effect of 20 mg YKYY017 observed on day 4 (−0.48 ± 0.27 log₁₀ copies/mL; 95% CI −1.01 to 0.06) provides encouraging signals for its potential efficacy against COVID-19. Even though the 95 % CIs of the effect size contained the null value, the differences between 10 mg and 20 mg group showed a potential dose-response pattern. Therefore, we are planning to proceed with the clinical development of a higher dose regimen of 20 mg YKYY017 twice daily for 5 days. A supplementary phase 1b trial using this intensified regimen has been completed with favorable tolerability profiles, supporting our plans to continue with phase 2/3 trial to further evaluate its efficacy and safety. Besides, approximately 15% of participants were excluded from the mITT population because their PCR tests were negative for the N gene. This exclusion rate is higher than the proportion assumed in our sample size calculations and may therefore reduce the statistical power of the analysis. Effect estimates beyond Day 4 were drawn from markedly smaller datasets due to missingness and therefore fluctuate more widely. Another factor that may affect the efficacy of the treatment is the participants’ severity of disease. In our trial, ~90% of the recruited participants had mild disease by NIH guideline criteria, with 20 mg group had the highest proportion of moderate disease participants (~15%). Besides, the coverage of risk factors and elder population is not optimal in this trial. Given the rapid decline of viral load among young and healthy people with mild diseases^11,12, it may be difficult for the antiviral treatment to show its impact on the disease course, and the medication might be more beneficial for the elderly population and people with more risk factors. In the planned new phase 2/3 trial, we will try to recruit a broader spectrum of patients to better reflect the antiviral effects of YKYY017.

Compared with oral and intravenous antiviral regimens, the inhaled nature of YKYY017 improves the efficiency of drug delivery to the lung and minimize systematic exposure, reducing the risk of potential drug-drug effects and systematic side effects^13,14. YKYY017 binds to the HR1 domain, a highly conserved region of the SARS-CoV-2 spike protein^8,15. Targeting on HR1 domain provides more stable antiviral effects against emerging SARS-COV-2 variants with immune-escaping mutations, a challenge commonly faced by monoclonal antibody therapies that interact with the receptor binding domain^6,7,16,17. The sequencing data in a subset of patients confirmed that the efficacy of YKYY017 was consistent among emerging SARS-CoV-2 Omicron subvariants such as HK.3.2, JN.1 and HK.3. Other inhaled antiviral therapies have been investigated in clinical trials for mild-to-moderate COVID-19 patients^18,19. In a phase 1/2 trial, inhaled monoclonal antibody cocktail therapy IBIO123 did not achieve the primary endpoint, showing a numerical decline in viral load change on Day 5 compared with placebo (−0.29 log₁₀ copies/mL, 95% CI: −1.32 to 0.75; p = 0.45)¹⁸. Similar to our trial, IBIO123 showed a nominal significant benefits in symptom-based secondary outcome¹⁸. Inhaled interferon beta-1a SNG001 did not show acceleration for viral load reduction and time to symptom improvement in a phase 2 trial¹⁹. The between-group difference of Day 3 viral load reduction from Day 0 was 0.27 log₁₀ copies/mL (95% CI: −0.28 to 0.82). Potential differences in time from symptom onset, sampling schedules, and patient characteristics indicate a cautious interpretation of cross-study comparisons.

Another notable finding of this study is that 20 mg YKYY017 might accelerate clinical recovery. For patients with mild to moderate COVID-19, persistent symptoms like cough remain a primary concern. Our study shows that inhaled 20 mg YKYY017 might accelerate symptom recovery by approximately one day, similar to some small-molecule oral antivirals^20,21. As an inhaled therapy, YKYY017 provides an alternative option with comparable clinical efficacy for patients, particularly those who may prefer non-oral medications or have difficulty with oral administration. However, it is worthwhile to note that, the primary outcome of our trial was not met, and no multiplicity adjustments were applied for the secondary outcomes. Therefore, the nominally significant results should be interpreted with caution and need to be validated in our planned new phase 2/3 trial.

The safety profile of inhaled YKYY017 was acceptable. The most common adverse events were hyperbilirubinemia and diarrhea, neither causing treatment discontinuation. Importantly, hepatic and renal dysfunction, frequently observed with oral or intravenous antiviral therapies, showed similar incidence between YKYY017 and placebo groups. No dose-response relationship in adverse events was observed between the 20 mg and 10 mg YKYY017 groups.

The trial has several limitations. The exclusion of people over 75 years of age and low recruitment numbers in the 60-75 age group limited the generalizability of the results to the elderly population. Besides, the representation of risk factors in the study was limited, with overweight or obesity being the predominant one. Additionally, most of the recruited patients had mild diseases. Our planned phase 2/3 trial, using the 5-day 20 mg YKYY017 twice daily regimen, will address these limitations by including a broader spectrum of patients, thereby allowing a more comprehensive assessment of the therapeutic potential across diverse populations and disease severities.

In summary, this phase 2 trial identified potential antiviral activity and clinical efficacy, as well as acceptable safety profile of inhaled 20 mg YKYY017. The relatively modest antiviral activity may reflect the insufficient dose, and we have now initiated a new phase 2/3 trial using a higher-frequency 20 mg YKYY017 regimen to further assess its efficacy.