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Pharmacodynamics: There are no relevant data on the pharmacodynamic effects of galcanezumab.
Clinical Studies: Migraine: The efficacy of PONTEVIA was evaluated as a preventive treatment of episodic or chronic migraine in three multicenter, randomized, double-blind, placebo-controlled studies: two 6-month studies in patients with episodic migraine (Studies 1 and 2) and one 3-month study in patients with chronic migraine (Study 3).
Episodic Migraine: Study 1 (NCT02614183) and Study 2 (NCT02614196) included adults with a history of episodic migraine (4 to 14 migraine days per month). All patients were randomized in a 1:1:2 ratio to receive once-monthly subcutaneous injections of PONTEVIA 120 mg, PONTEVIA 240 mg, or placebo. All patients in the 120 mg PONTEVIA group received an initial 240 mg loading dose. Patients were allowed to use acute headache treatments, including migraine-specific medications (i.e., triptans, ergotamine derivatives), NSAIDs, and acetaminophen during the study.
The studies excluded patients on any other migraine preventive treatment, patients with medication overuse headache, patients with ECG abnormalities compatible with an acute cardiovascular event and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening.
The primary efficacy endpoint for Studies 1 and 2 was the mean change from baseline in the number of monthly migraine headache days over the 6-month treatment period. Key secondary endpoints included response rates (the mean percentages of patients reaching at least 50%, 75%, and 100% reduction from baseline in the number of monthly migraine headache days over the 6-month treatment period), the mean change from baseline in the number of monthly migraine headache days with use of any acute headache medication during the 6-month treatment period, and the impact of migraine on daily activities, as assessed by the mean change from baseline in the average Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive domain score during the last 3 months of treatment (Months 4 to 6). Scores are scaled from 0 to 100, with higher scores indicating less impact of migraine on daily activities.
In Study 1, a total of 858 patients (718 females, 140 males) ranging in age from 18 to 65 years, were randomized. A total of 703 patients completed the 6-month double-blind phase. In Study 2, a total of 915 patients (781 female, 134 male) ranging in age from 18 to 65 years, were randomized. A total of 785 patients completed the 6-month double-blind phase. In Study 1 and Study 2, the mean migraine frequency at baseline was approximately 9 migraine days per month, and was similar across treatment groups.
PONTEVIA 120 mg demonstrated statistically significant improvements for efficacy endpoints compared to placebo over the 6-month period, as summarized in Table 1. PONTEVIA treatment with the 240 mg once-monthly dose showed no additional benefit over the PONTEVIA 120 mg once-monthly dose. (See Table 1 and Figures 1 and 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageFigure 3 shows the distribution of change from baseline in the mean number of monthly migraine headache days in bins of 2 days, by treatment group, in Study 1. A treatment benefit over placebo for PONTEVIA is seen across a range of changes from baseline in monthly migraine headache days. (See Figure 3.)
Click on icon to see table/diagram/imageFigure 4 shows the distribution of change from baseline in the mean number of monthly migraine headache days in bins of 2 days, by treatment group, in Study 2. A treatment benefit over placebo for PONTEVIA is seen across a range of changes from baseline in monthly migraine headache days. (See Figure 4.)
Click on icon to see table/diagram/imageChronic Migraine: Study 3 (NCT02614261) included adults with a history of chronic migraine (≥15 headache days per month with ≥8 migraine days per month). All patients were randomized in a 1:1:2 ratio to receive once-monthly subcutaneous injections of PONTEVIA 120 mg, PONTEVIA 240 mg, or placebo over a 3-month treatment period. All patients in the 120 mg PONTEVIA group received an initial 240 mg loading dose.
Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives), NSAIDs, and acetaminophen. A subset of patients (15%) was allowed to use one concomitant migraine preventive medication. Patients with medication overuse headache were allowed to enroll.
The study excluded patients with ECG abnormalities compatible with an acute cardiovascular event, and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening.
The primary endpoint was the mean change from baseline in the number of monthly migraine headache days over the 3-month treatment period. The secondary endpoints were response rates (the mean percentages of patients reaching at least 50%, 75% and 100% reduction from baseline in the number of monthly migraine headache days over the 3-month treatment period), the mean change from baseline in the number of monthly migraine headache days with use of any acute headache medication during the 3-month treatment period, and the impact of migraine on daily activities as assessed by the mean change from baseline in the MSQ v2.1 Role Function-Restrictive domain score at Month 3. Scores are scaled from 0 to 100, with higher scores indicating less impact of migraine on daily activities.
In Study 3, a total of 1113 patients (946 female, 167 male) ranging in age from 18 to 65 years, were randomized. A total of 1037 patients completed the 3-month double-blind phase. The mean number of monthly migraine headache days at baseline was approximately 19.
PONTEVIA 120 mg demonstrated statistically significant improvement for the mean change from baseline in the number of monthly migraine headache days over the 3-month treatment period, and in the mean percentage of patients reaching at least 50% reduction from baseline in the number of monthly migraine headache days over the 3-month treatment period, as summarized in Table 2. PONTEVIA treatment with the 240 mg once-monthly dose showed no additional benefit over the PONTEVIA 120 mg once-monthly dose. (See Table 2.)
Click on icon to see table/diagram/imageStudy 3 utilized a sequential testing procedure to control the Type-I error rate for the multiple secondary endpoints. Once a secondary endpoint failed to reach the required level for statistical significance, formal hypothesis testing was terminated for subsequent endpoints, and p-values were considered nominal only. In Study 3, PONTEVIA 120 mg was not significantly better than placebo for the proportion of patients with ≥75% or 100% reduction in migraine headache days. Patients treated with PONTEVIA 120 mg showed a nominally greater reduction in the number of monthly migraine headache days that acute medication was taken (-4.7 for PONTEVIA 120 mg vs. -2.2 for placebo; nominal p-value <0.001), and the mean change from baseline in the MSQ Role Function-Restrictive Domain score at Month 3 was nominally greater in patients treated with PONTEVIA 120 mg than in patients on placebo (21.8 for PONTEVIA 120 mg vs. 16.8 for placebo; nominal p-value <0.001). (See Figure 5.)
Click on icon to see table/diagram/imageFigure 6 shows the distribution of change from baseline in the mean number of monthly migraine headache days for the 3-month study period in bins of 3 days by treatment group. A treatment benefit over placebo for PONTEVIA is seen across a range of changes from baseline in monthly migraine headache days. (See Figure 6.)
Click on icon to see table/diagram/imagePharmacokinetics: Galcanezumab exhibits linear pharmacokinetics and exposure increases proportionally with doses between 1 and 600 mg.
A loading dose of 240 mg achieved the serum galcanezumab steady-state concentration after the first dose. The time to maximum concentration is 5 days, and the elimination half-life is 27 days.
Absorption: Following a subcutaneous dose of galcanezumab, the time to maximum concentration was about 5 days. Injection site location did not significantly influence the absorption of galcanezumab.
Distribution: The apparent volume of distribution (V/F) of galcanezumab was 7.3 L (34% Inter Individual Variability [IIV]).
Metabolism and Elimination: Galcanezumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
The apparent clearance (CL/F) of galcanezumab was 0.008 L/h and the elimination half-life of galcanezumab was approximately 27 days.
Specific Populations: Age, Sex, Weight, Race, Ethnicity: The pharmacokinetics of galcanezumab were not affected by age, sex, race, subtypes of migraine spectrum, or headache diagnosis based on a population pharmacokinetics analysis. Body weight has no clinically relevant effect on the pharmacokinetics of galcanezumab.
Patients with Renal or Hepatic Impairment: Renal and hepatic impairment are not expected to affect the pharmacokinetics of galcanezumab. Population pharmacokinetic analysis of integrated data from the galcanezumab clinical studies revealed that creatinine clearance did not affect the pharmacokinetics of galcanezumab in patients with mild or moderate renal impairment. Patients with severe renal impairment (creatinine clearance <30 mL/min) have not been studied. Based on a population PK analysis, bilirubin concentration did not significantly influence the CL/F of galcanezumab.
No dedicated clinical studies were conducted to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of galcanezumab.
Drug Interaction Studies: P450 Enzymes: Galcanezumab is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: The carcinogenic potential of galcanezumab has not been assessed.
Mutagenesis: Genetic toxicology studies of galcanezumab have not been conducted.
Impairment of Fertility: When galcanezumab (0, 30, or 250 mg/kg) was administered to male rats by subcutaneous injection prior to and during mating, no adverse effects on fertility was observed. The higher dose tested was associated with a plasma exposure (Cave, ss) 8 times that in humans at the recommended human dose (RHD) for migraine (120 mg). When galcanezumab was administered to female rats by subcutaneous injection in two studies (0, 30, or 100 mg/kg; 0 or 250 mg/kg) prior to and during mating and continuing throughout organogenesis, no adverse effects on fertility were observed. The highest dose tested (250 mg/kg) was associated with a plasma Cave, ss 38 times that in humans at 120 mg.
