Aims/Introduction This study evaluated the efficacy and safety of mirogabalin, a novel, potent, selective ligand of the α2δ subunit of voltage‐dependent Ca2+ channels, for the treatment of diabetic peripheral neuropathic pain (DPNP). Materials and Methods During this double‐blind, multisite, placebo‐controlled phase III study, Asian patients aged ≥20 years with type 1 or 2 diabetes and DPNP were randomized 2:1:1:1 to a placebo, mirogabalin 15, 20 or 30 mg/day for up to 14 weeks, with a 1‐ to 2‐week titration (NCT02318706). The primary endpoint was the change from baseline in average daily pain score (ADPS) at week 14, defined as a weekly average of daily pain (0 = no pain to 10 = worst possible pain, for the past 24 h). Results Of 834 randomized patients, 330, 164, 165 and 165 received placebo, mirogabalin 15, 20 or 30 mg/day, respectively, and were included in analyses (modified intention‐to‐treat population, n = 824); 755 (90.5%) completed the study. At week 14, the least squares mean average daily pain score change from baseline was −1.31, −1.34, −1.47 and −1.81, respectively, showing statistical significance for mirogabalin 30 mg/day versus placebo (P = 0.0027). The treatment‐emergent adverse events observed were mostly mild‐to‐moderate in all mirogabalin doses, and the most frequent treatment‐emergent adverse events were nasopharyngitis, somnolence, dizziness, peripheral edema and weight increase. Conclusions Mirogabalin relieved DPNP in a dose‐dependent manner; mirogabalin 30 mg/day showed statistically significant pain relief (vs placebo) in Asian DPNP patients. All doses of mirogabalin tested were well tolerated.

Mirogabalin has demonstrated a well-balanced profile of efficacy and safety and may provide an alternative therapeutic option for the treatment of postherpetic neuralgia.

1002 Background: Patritumab deruxtecan (HER3-DXd) is a novel, investigational ADC composed of a human anti-HER3 monoclonal antibody covalently bound to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Here we report updated safety and efficacy data from this ongoing study (U31402-A-J101; NCT02980341; JapicCTI-163401) of HER3-DXd in pts with previously treated MBC. Methods: U31402-A-J101 is a phase 1/2, multicenter, open-label, first-in-human study of HER3-DXd in pts with HER3-expressing MBC (N = 182). The study enrolled pts in dose-escalation (3.2-8.0 mg/kg IV Q3W) and dose-finding portions across molecular subtypes (n = 66; including HER2+ MBC, n = 14) followed by dose expansion in the following subtypes: HER3 high (4.8 mg/kg [n = 33] or 6.4 mg/kg [n = 31]), HER3 low (6.4 mg/kg [n = 21]) HR+/HER2− MBC or HER3-high TNBC (6.4 mg/kg [n = 31]). HER3-high and -low were defined as ≥75% and 25% ‒ < 75% membrane positivity. The primary objective was to assess safety and efficacy; secondary objectives included determining the relationship between efficacy and HER3 expression. Results: At data cutoff (16 Aug 2021), median study duration was 31.9 mo (range, 15-56). Median age was 57 y (range, 30-83); 132 (72.5%) and 50 (27.5%) pts had an ECOG PS of 0 or 1. Pts had a median of 5 (range, 1-13) prior lines of therapy for locally advanced/metastatic disease. Median treatment duration with HER3-DXd was 5.9 mo (range, 0.7-30.6). In a pooled evaluation of dose escalation/finding and expansion, efficacy is shown in pts with HR+/HER2− MBC, TNBC, and HER2+ MBC in the Table. Overall, 130 pts (71.4%) had grade ≥3 TEAEs; the most common (≥15%) were decreased neutrophil count (39.6%), decreased platelet count (30.8%), anemia (18.7%), and decreased white blood cell count (18.1%). 12 pts (6.6%) experienced treatment-related interstitial lung disease according to central adjudication, including 1 grade 5 event. Conclusions: A pooled analysis in this heavily pretreated population showed promising efficacy in pts with HR+/HER2− and HER2+ MBC as well as TNBC. The safety profile with longer follow-up is consistent with previous reports and showed adequate safety and tolerability. Studies are ongoing in MBC tumor types, with a focus on biomarkers associated with efficacy. Clinical trial information: NCT02980341. [Table: see text]

Aims/Introduction: Diabetic peripheral neuropathic pain (DPNP) affects the functionality, mood and sleep patterns of patients with diabetes. Mirogabalin, an a 2 d ligand with a slower dissociation for a 2 d-1 versus a 2 d-2 subunits, showed efficacy and safety in a randomized, double-blind, placebo-controlled, 14-week study in Asian patients with DPNP. This open-label extension study evaluated the long-term safety and efficacy of mirogabalin in Asian patients with DPNP. Material and Methods: This 52-week open-label extension study was carried out in Japan, Korea and Taiwan in patients with DPNP. Patients received mirogabalin, initiated at 5 mg twice daily and increased to a flexible maintenance dosage of 10 or 15 mg twice daily. Adverse events were monitored throughout the study. Patients provided a selfassessment of pain using the Short-Form McGill Pain Questionnaire. Results: Of the 214 patients who entered the study, 172 (80.4%) completed the extension study. Of 172 patients who completed the study, 149 received the highest dosage of mirogabalin (15 mg twice daily). The most common treatment-emergent adverse events were nasopharyngitis, diabetic retinopathy, peripheral edema, somnolence, diarrhea, increased weight and dizziness. Most treatment-emergent adverse events were mild or moderate in severity. The incidence of treatment-emergent adverse events leading to treatment discontinuation was 13.1%. The visual analog scale and all other Short-Form McGill Pain Questionnaire subscales (sensory score, affective score, total score and present pain intensity) generally decreased over time from baseline until week 52. Conclusions: This extension study showed the safety and efficacy of a long-term flexible dosing regimen of mirogabalin 10 or 15 mg twice daily in patients with DPNP.

Three phase 1 pharmacokinetic (PK)/pharmacodynamics (PD) studies were conducted in healthy men and women to further characterize the safety, tolerability, and PK/PD of mirogabalin administration with or without food and to guide the dose selection and regimen for phase 2 and 3 clinical development. The 3 studies included 2 randomized, double‐blind, placebo‐controlled, single‐ and multiple‐ascending‐dose studies, and 1 open‐label, crossover study to evaluate the PK of mirogabalin administered under fasting and fed (high‐fat meal) conditions. Forty‐eight and 47 healthy volunteers completed the single‐ and multiple‐dose studies, respectively. Thirty subjects were enrolled and completed the food effect study. Mirogabalin was well tolerated in the fed and fasted states. The most frequent treatment‐emergent adverse events (TEAEs)—dizziness and somnolence—were expected based on mirogabalin's mechanism of action. Subjects receiving the highest mirogabalin doses (50 and 75 mg single dose) showed greater dizziness and sedation and higher rates of TEAEs than subjects receiving 3‐30 mg. After oral administration, mirogabalin was rapidly absorbed (time to maximum concentration, ∼1 hour) and eliminated through urine unchanged (61%‐72% urinary excretion). Exposure increased in a dose‐proportional manner after single or multiple mirogabalin doses. No significant accumulation occurred with multiple doses over 14 days. After single doses of mirogabalin (15 mg), the bioavailability was considered equivalent in the fed and fasted states, indicating that mirogabalin can be taken without food restrictions. Based on these data, mirogabalin 15 mg twice daily was selected as the highest target dose for further clinical development.