Making Better Dose Decisions: Using Exposure‐Response Modeling to Integrate Efficacy Outcome of Two Phase IIb Clinical Trials of Ubrogepant for Migraine Treatment

Abstract

Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor antagonist in clinical development with positive phase III outcomes for acute treatment of migraine. This paper describes the population exposure-response (E-R) modeling and simulations, which were used to inform the phase III dose-selection rationale, based on ~ 800 participants pooled across two phase IIb randomized dose-finding clinical trials. The E-R model describes the placebo and ubrogepant treatment effects based on migraine pain end points (2-hour pain relief and 2-hour pain freedom) at various dose levels. Sensitivity analyses were conducted to evaluate various assumptions of placebo response in light of the high placebo response observed in one phase II trial. A population pharmacokinetic model describing the effect of formulations was included in the E-R simulation framework to assess potential dose implications of a formulation switch from phase II to phase III. Model-based simulations predict that a dose of 25 mg or higher is likely to achieve significantly better efficacy than placebo with desirable efficacy levels. The understanding of E-R helped support the dose selection for the phase III clinical trials. Migraine is a highly prevalent, disabling, and complex neurologic disorder characterized by debilitating headaches in conjunction with gastrointestinal and sensory alterations. 1-3 Calcitonin gene-related peptide (CGRP) is the most abundant neuropeptide in the trigeminal nerve and plays a key role in migraine pathogenesis. 3-5 Proof-of-concept for CGRP receptor antagonists (CGRP-RA) as potentially effective migraine treatment has been demonstrated with several compounds, including olcegepant (BIBN 4096), telcagepant (MK-0974), and MK-3207. 6-8 However, clinical development of both telcagepant and MK-3207 was stopped due to elevations in liver transaminase levels in a small number of patients. In a phase II clinical trial, ubrogepant (MK-1602), an oral, chemically distinct CGRP-RA, demonstrated efficacy without evidence of drug-induced liver injury when administered as a single dose. 9 The efficacy of ubrogepant was subsequently confirmed in two phase III trials (ACHIEVE I and ACHIEVE II), where clinical doses of 25, 50, and 100 mg were associated with improved efficacy compared with placebo. 10-12 Although clinical dose selection represents a challenge for any drug-development program, clinical dose selection for ubrogepant was further complicated by: (i) difficulty in

Ubrogepant: First Approval

“…An integrated exposure-response modeling analysis of this phase IIb study and another phase IIb study (NCT01657370) predicted that a dose of ubrogepant 25 mg or higher was likely to achieve significantly better efficacy than placebo with desirable efficacy levels. These data supported the ubrogepant dose selection utilized in the pivotal phase III trials [19].…”

Ubrogepant: Mechanism of action, clinical and translational science

“…Clinical doses greater than or equal to 25 mg were predicted to achieve targeted efficacy for 2‐h pain relief. In comparison, the higher doses of 50 and 100 mg were predicted to achieve targeted efficacy for 2‐h pain freedom in the exposure‐response analysis 22 …”

“…In support of phase III dose selection for ubrogepant, population pharmacokinetic modeling and exposure‐response analyses were performed utilizing data from two phase IIb studies 22 . The phase IIb trials consisted of a parallel dose‐finding/efficacy study ( N = 834 enrolled) and a smaller pharmacokinetics/efficacy ( N = 195 enrolled) study.…”

Novel Therapies in Acute Migraine Management: Small-Molecule Calcitonin Gene-Receptor Antagonists and Serotonin 1F Receptor Agonist

“…17 The findings of this trial were combined with its companion study (NCT01657370) to create an exposure-response module and determined that doses ≥25 mg were predicted to achieve significantly better efficacy. 30…”

“…17 The findings of this trial were combined with its companion study (NCT01657370) to create an exposure-response module and determined that doses ≥25 mg were predicted to achieve significantly better efficacy. 30 Ubrogepant doses of 25, 50, and 100 mg were further studied in the 2 phase III, randomized, single-attack, placebo-controlled trials, ACHIEVE I 28 and ACHIEVE II, 29 published in 2019. Both ACHIEVE I and ACHIEVE II enrolled patients 18 to 75 years of age with at least a 1-year history of migraine with or without aura according to ICHD-III beta criteria.…”