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Skoreński et al. Rare Dis Orphan Drugs J 2023;2:6 https://dx.doi.org/10.20517/rdodj.2022.21 Page 19 of 23

Figure 19. Synthetic substrates and ABPs of NSP4.

Another phase II clinical trial of an HNE inhibitor called ONO-6818 in patients with cystic fibrosis did not
meet its primary endpoint of improving lung function compared to a placebo. A phase I clinical trial of an
HNE inhibitor called M3364 in patients with advanced solid tumors showed that the drug was well-
tolerated and had some anti-tumor activity, with one patient experiencing a partial response and several
others having stable disease.

The reasons for the failure of HNE inhibitors in clinical trials are multifactorial. One possible explanation is
the complexity and heterogeneity of the diseases that HNE inhibitors are targeting. For example, COPD and
cystic fibrosis are characterized by chronic inflammation, but there are multiple underlying causes and
factors that contribute to the disease pathogenesis. Therefore, targeting HNE alone may not be sufficient to
achieve clinical benefits. Another challenge is the difficulty in achieving optimal pharmacokinetic and
pharmacodynamic properties of HNE inhibitors. In some cases, the HNE inhibitors may not be sufficiently
potent or selective to effectively inhibit HNE in vivo, or they may be rapidly metabolized or eliminated from