Justification for Dose. Section 6.7 Dose Modification of ALXN2050 Revised the criteria for dose escalation to 180 mg bid to be based on clinical response and tolerability as defined for each patient group in the dose modification section (Section 6.7). To clarify dose escalation process
Justification for Dose. Clinical PK and PD data have been generated for ALXN2050 in single ascending and multiple ascending doses in healthy volunteers (Studies ACH228-001 and ACH228-002, respectively). In these Phase 1 healthy volunteer studies, ALXN2050 PK exposures increased dose-proportionally following a single dose administration, and in a greater-than-dose-proportional manner following multiple doses at steady state over the dose range of 40 mg bid to 200 mg bid. Corresponding PD activity as determined by AP inhibition increased with increasing exposure. In the multiple-dose Study ACH228-002, the dosage regimens of both 120 mg bid and 200 mg bid were safe and effective, showing approximately 10-fold or greater safety margin in both maximum plasma concentration (Cmax) and the area under the concentration-time curve from time zero to 24 hours (AUC0-24) over the exposures achieved at the no observed adverse effect level (NOAEL) from nonclinical chronic toxicology studies (see Investigator’s Brochure). In addition, both dosage regimens provided complete (> 90%) and sustained inhibition of AP activity throughout the 12-hour dosing interval. However, large variabilities were observed in the PK and PD data and in the established PK/PD relationship. Intersubject variability in PK and the PK/PD relationship indicated that a dosage higher than 120 mg bid, such as 180 mg bid, may be required to ensure more participants reach and maintain an ALXN2050 concentration above the threshold for 90% AP inhibition. Based on the favorable clinical safety and tolerability data from these studies and the PK and PD characterization of ALXN2050, these results indicate that 120 mg bid of ALXN2050 would be a safe and efficacious starting dose for proposed human studies in patients with PNH. Based on data from the Phase 1 studies, the starting dose regimen will be 120 mg bid, with a dose titration option available (if additional efficacy is anticipated) to 180 mg bid.
Justification for Dose. The 30-mg dose selected for this study in healthy participants is within the 15 to 60 mg daily dose range that has demonstrated an acceptable safety profile in healthy volunteers and patients with WD in Phase 1 to Phase 3 clinical studies. Repeated doses between 15 and 60 mg/day have been tested in the Phase 2 Study WTX101-201 and are being tested in the ongoing Phase 3 Study WTX101-301. A single oral dose of 60 mg has been tested in healthy volunteers in Phase 1 Studies WTX101-101, WTX101-102, and WTX101‑HV-106, and has been well tolerated. While most studies used high doses (120-300 mg/day or greater) of tetrathiomolybdate to rapidly deplete total body Cu as measured by ceruloplasmin, Lin et al reported use of bis-choline tetrathiomolybdate (ALXN1840) at a more modest dose of 30 mg/day in prostatic malignancy administered in 28‑day cycles (Lin, 2013). At this dose, only a moderate reduction in ceruloplasmin was reported with the median value remaining just above 20 mg/dL (reference range: 20‑35 mg/dL). Only one Grade 3 hematologic finding of leukopenia was reported at this dose (during the study, which included up to four 28‑day cycles of ALXN1840). The proposed dosing period for this study is half that of a single 28-day cycle, for which reports indicate that the safety risk is acceptable with adequate monitoring and management (Xxx, 2013). In addition to its use in both patients with WD and healthy volunteers, tetrathiomolybdate, the active anion in ALXN1840, has been used in a substantive number of oncology programs, and based on published data, bis-choline tetrathiomolybdate (ALXN1840) has been well tolerated up to a maximum tolerated repeated dose of 300 mg/day (Lowndes, 2008). Early oncology programs employed an induction approach with the use of high doses of tetrathiomolybdate followed by lower maintenance doses and used serum ceruloplasmin as a marker for depletion of total body Cu, with a target ceruloplasmin concentration between 5 and 15 mg/dL (Xxxxxxx, 2008; Xxxxxx, 2000; Xxx, 2013; Pass, 2008; Xxxxx, 2006). The most commonly reported AEs in oncology programs include fatigue, dizziness, myelosuppression (anemia, leukopenia, neutropenia, lymphocytopenia and/or thrombocytopenia), and gastrointestinal complaints (nausea, vomiting, diarrhea, constipation, flatulence, sulfur burps, anorexia). With the exception of the gastrointestinal complaints, reported AEs have largely been associated with over- decoppering. Myelosuppression is monitorable and...
Justification for Dose. This study is a proof-of-concept study that will evaluate the effect of vibegron in subjects with IBS-D or IBS-M. The dose of vibegron for this study (75 mg once daily) is the same dose that was evaluated in the recent Phase 3 program for subjects with overactive bladder. The evidence to support this dose comes from the following data: • Several Phase 2 and Phase 3 clinical studies with vibegron at doses up to 100 mg (including 75 mg) have demonstrated that it is generally safe, well tolerated, and efficacious in subjects with overactive bladder over 52 weeks of treatment: o Vibegron 75 mg (2 Phase 3 studies): Studies 3003 and 3004 o Vibegron 50 mg and 100 mg (2 Phase 3 studies and 1 Phase 2b study): Studies 301, 302, and 008 • Study 008 demonstrated dose-dependent significant efficacy over placebo across multiple clinical endpoints in overactive bladder, with the maximal effect generally estimated at doses between 50 and 100 mg • Compared with placebo, no clinically relevant differences in heart rate or blood pressure were observed for vibegron (50 and 100 mg once daily) in the overactive bladder population • Vibegron 75 mg administered once daily is expected to capture approximately 90% of the efficacy of 100 mg daily; the mean trough concentration for vibegron 75 mg at steady-state is 40 ng/mL, which is several fold above the β3 half-maximal effective concentration of 1.7 nM (0.76 ng/mL) The dose of vibegron used in this IBS study (75 mg once daily) is expected to have a similar safety profile to that observed with the same dose in the overactive bladder population.
