Background Janus kinase (JAK) enzymes play key roles in cytokine signaling and are important in the pathology of autoimmune diseases. ASP015K is an oral JAK inhibitor with selectivity for JAK1/3 over JAK2 and is in development for treatment of autoimmune diseases (eg, rheumatoid arthritis [RA]).
Objectives Assessment of safety of ASP015K in 13 phase 1 and 2 clinical trials completed in healthy volunteers (HVs) and patients (pts).
Methods Safety profile of ASP015K, as measured by adverse events (AEs), was assessed in completed ASP015K trials including: 11 pharmacokinetic (PK), drug-drug interaction (DDI), or biopharmaceutics studies in HVs, 1 PK/DDI study in RA pts, and 1 efficacy and safety study in psoriasis pts. ASP015K was given as single doses (3–300 mg) or repeated doses ranging from 20–400 mg daily for a duration of 7–42 days. Treatment-emergent AEs (TEAEs), drug-related AEs (DRAEs), and serious AEs (SAEs) were evaluated.
Results AEs from 521 subjects (382 HVs and 139 pts) were pooled and summarized. Of these, 77 were treated with placebo (PBO) and 444 with ASP015K. Overall, 216 (41.5%) HVs/pts reported a TEAE (PBO, 19 [24.7%]; ASP015K, 197 [44.4%]). DRAEs were reported in 12 (15.6%) PBO and 131 (29.5%) ASP015K HVs/pts. The most common TEAEs in the PBO vs ASP015K groups were headache (3.9% vs 8.8%), diarrhea (3.9% vs 6.8%), flatulence (1.3% vs 3.6%), nausea (0% vs 3.6%), neutropenia (1.3% vs 3.4%), abdominal pain (1.3% vs 2.9%), and vomiting (0% vs 2.3%). These AEs were generally mild or moderate in severity. Similar to TEAEs, the most common DRAEs in the PBO vs ASP015K groups were headache (2.6% vs 7.4%), diarrhea (2.6% vs 5.9%), neutropenia (1.3% vs 3.4%), nausea (0% vs 3.2%), flatulence (1.3% vs 2.9%), and abdominal pain (1% vs 2.7%). TEAEs of blood and lymphatic disorders occurred in 1.3% and 3.4% of PBO and ASP015K HVs/pts, respectively, and all were considered DRAEs, and no AEs of anemia were reported in either treatment group. The percentage of TEAEs classified as infections was similar between groups (6.5% for PBO vs 5.9% for ASP015K). Infection DRAEs were also similar (1.3% vs 2.0%). One TEAE of herpes simplex in the ASP015K group was reported; there were no reported tuberculosis cases. Fewer HVs/pts in the PBO group had DRAEs related to investigations (2.6% vs 3.6% for ASP015K); the most common investigations were neutrophil count decreased (0% vs 1.1%). Overall, no deaths were reported and only 2 SAEs (gastroenteritis/urinary tract infection) were reported in 1 RA pt in the ASP015K group, which occurred prior to study drug dosing.
Conclusions ASP015K administered as single or multiple doses for up to 42 days was safe and well tolerated in HVs/pts in 13 phase 1 and 2 studies. The most frequent TEAEs were GI disorders, which were generally mild or moderate. Neutropenia was observed with ASP015K and is consistent with its mechanism of action. There was no increase in infections, including opportunistic infections, associated with ASP015K, nor was there any apparent difference between the treatment groups in types of infections. Additional phase 2b studies to evaluate the safety and efficacy of ASP015K in RA are ongoing.
Disclosure of Interest J. Garg Employee of: Astellas Pharma Global Development, Inc., G. Ball Employee of: Astellas Pharma Global Development, Inc., Y. Cao Employee of: Astellas Pharma Global Development, Inc., T. Zhu Employee of: Astellas Pharma Global Development, Inc., R. Tarzynski-Potempa Employee of: Astellas Pharma Global Development, Inc., S. Wisseh Employee of: Astellas Pharma Global Development, Inc.
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