Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size

Abstract

Objective Chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilia is a disease of the upper respiratory tract for which few therapies are available. Because the oral investigational drug dexpramipexole serendipitously decreased blood eosinophils in amyotrophic lateral sclerosis studies, we assessed its safety, eosinophil‐lowering activity, and preliminary clinical efficacy in patients with CRSwNP and eosinophilia. Methods Sixteen subjects with CRSwNP, absolute eosinophil count (AEC) ≥ 0.300 × 109/L, and polyp tissue eosinophils were evaluable for efficacy in a 6‐month open‐label, multi‐center study of dexpramipexole 150 mg twice daily. The coprimary endpoints were change in AEC and change in total polyp score (TPS) from baseline to month 6, with additional clinical and histologic endpoints assessed. Results Thirteen of 16 subjects completed 6 months of dexpramipexole treatment. Geometric mean baseline AEC was 0.525 ± 0.465 eosinophils × 109/L and decreased to 0.031 ± 0.019 after 6 months of dexpramipexole treatment, a 94% reduction (P < 0.001). Ten of 16 subjects had eosinophil counts reduced to ≤ 0.020 × 109/L at month 6. In 12 subjects with nasal polyp biopsies at baseline and month 6, tissue eosinophils were reduced from a mean of 168 ± 134 to 5 ± 2 per high‐power field (HPF) (P = 0.001), a 97% reduction from baseline. There was no significant reduction in TPS or improvement in other clinical endpoints. Dexpramipexole was well tolerated, with no drug‐related serious adverse events. Conclusion Dexpramipexole treatment produced profound eosinophil‐lowering in peripheral blood and nasal polyp tissue. Despite the near‐elimination of polyp eosinophils, decreased TPS and nasal symptom improvement were not observed. Level of Evidence 2 Laryngoscope, 129:E61–E66, 2019

IL-5Rα marks nasal polyp IgG4 and IgE-secreting cells in aspirin-exacerbated respiratory disease

“…47 However, another recent study of dexpramipexole, an experimental drug that depletes nearly all eosinophils from within the nasal polyp tissue, failed to show any symptomatic improvement or any reduction in nasal polyp size. 48 Taken together with our current findings, we suspect that IL-5targeting monoclonal antibodies may alter the survival and function of IL-5Rα + antibodysecreting cells, which may contribute to the mechanism of their therapeutic benefit. IgG and IgA isotype heavy chain regions (IGHG1, IGHG2, IGHG3, IGHG4, IGHA1, IGHA2), (D) the immunoglobulin E heavy chain (IGHE), and (E) the IL-5 receptor alpha chain (IL5RA).…”

Biologics for chronic rhinosinusitis with nasal polyps

“…38 Interestingly, there are some contradictory studies and doubts on the role of eosinophils, which may need further explanation. 64,65 However, mepolizumab, reslizumab, and benralizumab reduce blood and tissue eosinophil counts, reduce corticosteroid dependence and asthma exacerbations, and are approved for the treatment of severe eosinophilic asthma. [66][67][68] Their effectiveness also has been demonstrated for CRSwNP, with mepoliumab and benralizumab currently in phase 3 trials.…”

Biologics in chronic rhinosinusitis with nasal polyposis

“…However, we may need to resist the impulse to then assume that eosinophils themselves should be directly targeted with therapeutics, because anti-eosinophil trials have not shown great success for CRSwNP. 31,32 Interestingly, immunoglobulin levels are also globally increased within nasal polyp tissue, including IgE and autoantibodies of all isotypes. 30,[33][34][35] Furthermore, although plasma IgE levels are also increased in patients with CRSwNP, there is no association of these IgE levels with the presence of atopy or environmental allergies.…”