This Phase 3 study did not demonstrate efficacy of reparixin as compared with placebo in adults for severe COVID-19 pneumonia. Nonetheless, there was a positive trend in favor of reparixin in the primary and the secondary efficacy endpoints. More patients in the reparixin group were alive and free of respiratory failure at Days 28 and 60, fewer patients died by Day 28, fewer needed to be transferred to ICU for deterioration of respiratory status, and more had a meaningful recovery. This was consistently supported by the other endpoints; for example, reparixin was associated with statistically significant improvements in the exploratory analyses of serious events, i.e., invasive mechanical ventilation use or ECMO followed by death up to Days 28 and 60, indicating that reparixin may prevent the most invasive rescue treatments that are frequently linked to death. Furthermore, patients in the reparixin group started improving earlier, with significant differences in clinical status and oxygenation status on Day 3 (the first post-dose assessment).

The COVID-19 pandemic has led to close to 7 million deaths worldwide, with 1 million deaths being reported in the USA alone [20], and millions more affected directly and indirectly through impacts on their livelihood, employment opportunities, education, and long-term health-related quality of life. However, the impact of COVID-19 on respiratory pathology, along with the efforts taken to manage the disease, have not only reshaped our awareness of viral pneumonias, but has helped to advance the way we manage patients with infection-related acute hypoxemic respiratory failure.

Pharmacologic management of COVID-19, other than anti-virals, has focused on therapies that modulate the hyperinflammatory state effected by the excessive production of cytokines by a deregulated immune system, which is increasingly recognized as a key feature of severe COVID-19 [21]. Such immunomodulators include steroids, IL-6 inhibitors, and Janus kinase (JAK) inhibitors. The large RECOVERY study demonstrated a significant drop in mortality following early low-dose dexamethasone in patients with COVID-19, with the greatest benefit seen in mechanically ventilated patients whereas there was no benefit for those not requiring supplemental oxygen [22]. Unfortunately, this benefit is associated with significant drawbacks, especially when the use of steroids is protracted, in particular beyond the currently advised 10 days. Indeed, a meta-analysis of 21,350 patients with COVID-19 concluded that the overall effect of steroids on COVID-19-related mortality is less certain than anticipated, with the caveat that there was great heterogeneity among the studies reviewed [23]. When added to steroids, tocilizumab, the most widely used IL-6 receptor inhibitor, led to an improvement of in-hospital mortality—although when optimal SoC was applied this benefit was observed only among the sickest patients [24]. Furthermore, the risk of late-onset infectious complications due to tocilizumab exposure remains a concern [25]. This becomes even more of an issue with inhibition of the JAK–STAT pathway through the use of JAK inhibitors, since the involvement of JAKs in the immune response, especially via interferon-gamma, means that their potential adverse events include immunosuppression with reactivation of latent infection or development of new secondary infections, compounded by thrombotic events, cardiotoxicity, and hepatotoxicity [26].

IL-8 is one of the main neutrophil chemoattractors in the lung. Neutrophils abound in the lungs of patients with fatal COVID-19 [2, 3] and their activation-related functions such as the production of reactive oxygen species, proteases, inflammatory mediators, and release of NETs can result in local tissue injury. NETs are a constant histopathologic feature in the lungs of patients with fatal COVID-19, where their spatial distribution correlates closely with local IL-8 levels [27]. In fact, IL-8 together with other ELR+CXCL (i.e., those with the amino acid sequence Glu-Leu-Arg present) chemokines acting on CXCR1 and CXCR2, are among the most effective NET promoters [28, 29], both persistent and out of proportion to tissue viral load [27]. IL-8 pathway activation is a marker of disease status with serum levels increasing in correlation with progression of disease severity in patients with COVID-19 [30]. Our previous experience with reparixin supported further exploration of the role of IL-8 inhibition in severe COVID-19.

The current study was designed on assumptions informed by the first wave of COVID-19 that approximately 60% of patients in the placebo group would be alive and free of respiratory failure at Day 28, with a difference ≥ 20% in favor of reparixin. These assumptions were not confirmed, given the rapidly evolving natural history and treatment options for COVID-19. In our previous Phase 2 study in a similar patient population, 42.1% of patients in the placebo group experienced the composite endpoint of need for supplemental oxygen or mechanical ventilation use, ICU admission, or requirement of rescue medication by Day 28 (compared with 16.7% in the reparixin group) [17]. In addition, 15.8% of patients in this group died, whereas in the current study mortality by Day 28 was 8.6% in the placebo group and 6.0% in the reparixin group. Given that the patients enrolled in the two studies had comparable COVID-19 severity (as assessed using WHO-OS), the difference in outcomes is most likely attributable to the adaption of new therapies for COVID-19 that became SoC in the meantime, as well as changes in the proportion of vaccinated patients and changes in disease epidemiology and natural history. As disease-related mortality decreases, therapies that have demonstrated a positive effect on survival during the first wave of the disease are likely to lose this effect in subsequent studies. As an example, in the latest tocilizumab study, REMDACTA [24], which failed to demonstrate a survival benefit, mortality in both groups (18% versus 20% with tocilizumab versus placebo, respectively) was much lower than that in the RECOVERY and REMAP-CAP studies that established a mortality benefit (REMAP-CAP, 28% versus 36%; RECOVERY 31% versus 35% [31, 32]).

Lack of mortality benefit, however, does not equate to lack of efficacy, and our results demonstrate a beneficial effect of reparixin on important patient-centered outcomes such as transfer to ICU for deterioration of respiratory status. Even 1 day away from the ICU or not intubated translates to considerable gains in psychological strain for patients and their families and financial cost [33,34,35]. Reparixin appears to assist in achieving this goal, thus adding to the COVID-19 armamentarium in a meaningful way. Furthermore, and in contrast to other COVID-19 therapies [23, 36,37,38], reparixin was not associated with any safety signals, and was very well tolerated. Compared with those receiving placebo, fewer patients in the reparixin group had TEAEs, overall, serious, treatment-related, or severe TEAEs, or TEAEs leading to treatment discontinuation or death. Given that the most commonly reported TEAEs were related to the underlying disease (e.g., respiratory failure or respiratory distress), the fact that patients receiving reparixin experienced fewer AEs is a further indication of efficacy. Consistently with the previous trials [17, 39], there was a very low incidence of secondary infection despite the widespread use of glucocorticoids.

The main limitation of the study is that, because it was conducted during a surge of the pandemic in Italy, study conduct was at times difficult, leading to a high amount of missing clinical and pharmacokinetic data, especially at later time points. Furthermore, the identity and prevalence of SARS-CoV-2 variants in patients participating in the study are unknown, as the majority of the participating centers did not have access to variant screening methods. However, during the study period, the SARS-CoV-2 alpha variant was predominant, corresponding to an increase in infections during the second wave of the epidemic, whereas the omicron variant and its sublineages, which emerged in South Africa in November 2021, were not included in the study [40]. Moreover, there was a rapid change in the prevailing SARS-CoV-2 variant in Italy during the conduction of the study, with prevalence of the alpha variant increasing from 3.5% in December 2020 to 86.7% by March 2021 [40]. Given that evolving viral strains differ in their ability to evade host immunity, it is unclear whether an immune modulator that acts primarily through regulation of neutrophil activation would have the same efficacy across variants. In addition, the attempt to collect inflammatory markers to investigate the link between inflammatory status and drug efficacy was not successful. Finally, although the proportion of patients with concomitant glucocorticoid use was collected, the length of administration was not captured in the study database.