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Pharmacology: Pharmacodynamics: Mechanism of action: Eptinezumab is a humanized immunoglobulin G1 (IgG1) antibody that binds to α- and β-forms of human calcitonin gene-related peptide (CGRP) ligand with low picomolar affinity (4 and 3 pM KD, respectively). This, in combination with the 100% bioavailability following an IV administration, translates into fast blockage of the biological effects of circulating CGRP in humans. As a result, eptinezumab prevents the activation of the CGRP receptors and hence the downstream cascade of physiological events linked to initiation, frequency and severity of migraine attacks.
Eptinezumab is highly selective and does not bind to any of the related neuropeptides amylin, calcitonin, adrenomedullin and intermedin.
Pharmacodynamic effects: Pharmacodynamic activity characterized by inhibition of α-CGRP-mediated neurogenic vasodilation induced by topical capsaicin relative to baseline was evaluated following single or multiple administrations of eptinezumab in human volunteers. Mean neurogenic induced vasodilation was reduced by 41% following intravenous 100 mg eptinezumab administration compared to an increase of 12% for placebo on the day following treatment. For up to 12 weeks, the reduction persisted ranging from 20% to 50% for 100 mg eptinezumab while placebo ranged from a 20% increase to 0.20% reduction during the same period.
Clinical efficacy and safety: VYEPTI was evaluated for the preventive treatment of migraine in two pivotal placebo-controlled studies: PROMISE 1 was conducted in patients with episodic migraine (n=888) and PROMISE 2 in patients with chronic migraine (n=1072). Enrolled patients had a history of migraine (with or without aura) of at least 12 months, according to the International Classification of Headache Disorders (ICHD-II or III) diagnostic criteria.
The long-term safety of VYEPTI following repeated dosing for up to 2 years was further evaluated in patients with chronic migraine in an open-label study, PREVAIL, (n=128).
The efficacy of VYEPTI was also evaluated during a migraine attack occurring in patients who were candidates for preventive treatment of migraine: RELIEF was conducted in patients with migraine as defined by ICHD-3 with ≥4 and ≤15 migraine days per month in the 3 months prior to screening (n=480).
PROMISE 1: Episodic Migraine: PROMISE 1 was a parallel group, double-blind, placebo-controlled global study to evaluate the efficacy and safety of VYEPTI for the preventive treatment of episodic migraine (defined as ≤14 headache days of which at least 4 migraine days during the past 3 months and confirmed during the 28-day screening period) in adults. 665 patients were randomized to placebo (N=222), 100 mg eptinezumab (N=221), or 300 mg eptinezumab (N=222) every 12 weeks for 48 weeks (4 infusions). Patients were allowed concurrent acute migraine or headache medications, including migraine-specific medications (i.e., triptans, ergotamine derivatives), during the study. Regular use (greater than 7 days per month) of other treatments for the prevention of migraine was not allowed.
The primary efficacy endpoint was the change from baseline in mean monthly migraine days (MMD) over Weeks 1-12. The key secondary endpoints included ≥50% and ≥75% migraine responder rates defined as the proportion of patients achieving at least the specified percent reduction in migraine days over Weeks 1-12, ≥75% migraine responder rate over Weeks 1-4, and the percentage of patients with a migraine on the day after the first dosing (Day 1).
Patients had a mean age of 40 years (range: 18 to 71 years), 84% were women, and 84% were white. The mean number of migraine days per month at baseline was 8.6 and the rate of patients with a migraine on a given day was 30.7% during the screening period; both were similar across treatment groups.
The 4-week results over Weeks 1-48, following four quarterly infusions of VYEPTI treatment are presented as changes from baseline in mean MMD (Figure 1). Both VYEPTI 100 mg and 300 mg treatment groups demonstrated statistically significant and clinically meaningful greater improvements from baseline to week 1-12 compared to placebo on mean MMD. For both doses of VYEPTI, a greater mean decrease in MMDs compared to placebo was observed from the first day after administration and was sustained for all timepoints through Week 48. (See Figure 1.)
Click on icon to see table/diagram/imageAt each timepoint, an ANCOVA including treatment and prophylactic medication use as factors and baseline migraine days as a continuous covariate was used to estimate the mean change from baseline.
For both doses of VYEPTI the preventive treatment benefit over placebo was observed as early as Day 1 post-infusion in a prespecified analysis. The percentage of patients with a migraine on the day after dosing were lower for both the 300 and the 100 mg groups relative to placebo (13.9% (p=0.0159) and 14.8% (p=0.0312)), respectively compared to 22.5% on Day 1.
VYEPTI treatment demonstrated statistically significant and clinically meaningful improvements for primary and key secondary efficacy endpoints, as summarized in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageAdditional secondary efficacy endpoints in PROMISE 1 substantiated results from the key efficacy endpoints. In line with the ≥50% and ≥75% migraine responder rates, 100% migraine responder rates (average of 4-week means across Weeks 1-12) were higher for both doses of VYEPTI compared to placebo (100 mg and 300 mg: 11.4% and 16.8% vs placebo: 9.1%).
PROMISE 2: Chronic Migraine: PROMISE 2 was a parallel group, double-blind, placebo-controlled global study to evaluate the efficacy and safety of VYEPTI for the preventive treatment of chronic migraine (defined as ≥15 headache days, of which ≥8 were assessed as migraine days in the 3 months prior to screening and confirmed during the 28-day screening period) in adults. A total of 1,072 patients were randomized and received placebo (N=366), 100 mg eptinezumab (N=356), or 300 mg eptinezumab (N=350) every 12 weeks for 24 weeks (2 infusions). During the study, patients were allowed acute or preventive medication for migraine or headache on an established stable regimen (except for onabotulinumtoxinA). A total of 431 patients (40%) with a dual diagnosis of chronic migraine and medication overuse headache (associated with the overuse of triptans, ergotamine, or combination analgesics >10 days/month, or acetaminophen, acetylsalicylic acid, or non-steroidal anti-inflammatory drugs ≥15 days/month) confirmed during the 28 days screening period were included in the study population. Patients taking opioids or butalbital containing products >4 days/month were excluded.
The primary efficacy endpoint was the change from baseline in mean MMD over Weeks 1-12. The key secondary endpoints included ≥50% and ≥75% migraine responder rates defined as the proportion of patients achieving the specified percent reduction in migraine days over Weeks 1-12, ≥75% migraine responder rate over Weeks 1-4, the percentage of patients with a migraine on the day after dosing, the reduction in migraine prevalence from baseline to Week 4, the change from baseline in the total score on the Headache Impact Test (HIT-6) at Week 12 (300 mg dose only), and the change from baseline in acute monthly migraine medication days, mean over Weeks 1-12 (300 mg dose only). The HIT-6 is a self-administered questionnaire assessing the impact of headache on the functional status of patients with migraine. Interpretation of the impact of migraine on daily function by total score is as follows: 60-78 = Severe; 56-59 = Substantial, 50-55 = Some, and 36-49 = little to none. A clinically meaningful change (i.e response) is defined as a within person decrease from baseline of at least 5 points.
A health-related quality of life secondary endpoint was the Short-Form Health Survey Version 2 (SF-36v2). The SF-36v2 measures functional health and well-being from the patient's point of view. It comprises 36 questions which cover eight domains of health measuring quality of life over the past 4 weeks. The eight sections measured are vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health. A clinically meaningful change (i.e. response) is defined as an increase of at least 3 points from baseline.
Patients had a mean age of 41 years (range: 18 to 65 years), 88% were women, and 91% were white. Forty-one percent of patients were taking concomitant preventive medication for migraine. The mean number of migraine days per month at baseline was 16.1 and the rate of patients with a migraine on a given day was 57.6% during the screening period; both were similar across treatment groups.
The monthly results over Weeks 1-24, following repeated VYEPTI infusions every 12 weeks are presented as changes from baseline in mean MMD (Figure 2). Both VYEPTI 100 mg and 300 mg treatment groups demonstrated statistically significant and clinically meaningful greater improvements from baseline to week 1-12 compared to placebo on mean MMD. For both doses of VYEPTI, a greater mean decrease in MMDs compared to placebo was observed from the first day after administration and was sustained for all timepoints through Week 24. (See Figure 2.)
Click on icon to see table/diagram/imageAt each timepoint, an ANCOVA including treatment as a factor and baseline migraine days as a continuous covariate was used to estimate the mean change from baseline.
A preventive treatment benefit over placebo for both doses of VYEPTI was observed as early as Day 1 post-infusion in a prespecified analysis. There was a statistically significant lower frequency in day 1 migraine for both the 300 and 100 mg groups compared to placebo (27.8% [p< 0.0001] and 28.6% [p<0.0001]), respectively, compared to 42.3%, on Day 1.
Eptinezumab treatment demonstrated statistically significant and clinically meaningful improvements for key efficacy endpoints as summarized in Table 2. (See Table 2.)
Click on icon to see table/diagram/imageAdditional secondary efficacy endpoints in PROMISE 2 substantiated results from the key efficacy endpoints. In line with the ≥50% and ≥75% migraine responder rates, 100% migraine responder rates (average of 4-week means across Weeks 1-12) were higher for both doses of VYEPTI compared to placebo (100 mg and 300 mg: 10.8% [0.8; 9.1] and 15.1% [6.2; 15.5] vs placebo: 5.1%).
In the 431 (40%) patients from PROMISE 2 diagnosed with medication overuse headache, the difference in the reduction of mean monthly migraine headache days observed between VYEPTI and placebo was -3.0 days and -3.2 for 100 mg and 300 mg, respectively.
RELIEF: Initiation of preventive treatment during a migraine attack: RELIEF was a randomized, parallel group, double-blind, placebo-controlled study to evaluate the efficacy of VYEPTI when initiated during a migraine attack occurring in patients who were candidates for preventive treatment of migraine as defined by ICHD-3 with ≥4 and ≤15 migraine days per month in the 3 months prior to screening. A total of 480 patients were randomized to receive a single infusion of either VYEPTI 100 mg or placebo in a 1:1 ratio. Treatment was initiated within 1 to 6 hours on the onset of a qualifying migraine attack.
During the study, patients were allowed rescue medication, defined as any medication to treat migraine or migraine associated symptoms, any time after 2 hours post-start of VYEPTI infusion. During the study, patients were allowed to use preventive medication for migraine or headache on an established stable regimen. Other anti-CGRP treatments were prohibited during the study.
The co-primary endpoints were time to headache pain freedom and time to absence of most bothersome symptom (selected among nausea, photophobia and phonophobia). The key secondary endpoints included headache pain freedom at 2 hours after the start of infusion and absence of most bothersome symptom at 2 hours after the start of infusion.
Patients had a mean age of 44 years (range: 18 to 75 years), 84% were women, and 86% were white. 16.4% of patients were taking concomitant preventive medication for migraine.
VYEPTI treatment demonstrated statistically significant and clinically meaningful improvements for primary and key secondary efficacy endpoints, as summarized in Table 3. (See Table 3.)
Click on icon to see table/diagram/imageThe safety profile observed in RELIEF is consistent with the safety profile observed in the two pivotal placebo-controlled studies with VYEPTI (PROMISE 1 and 2).
PREVAIL: Long-term study: VYEPTI 300 mg was administered every 12 weeks by IV infusion in patients with chronic migraine in an open-label study for up to 2 years, with the primary objective of further evaluating the long-term safety following repeated doses of VYEPTI. Secondary objectives included characterization of the PK and immunogenicity profiles for VYEPTI (Adverse Reactions) and evaluation of the therapeutic effect of VYEPTI on several patient reported outcomes relating to quality of life and headache impact including the Headache Impact Test (HIT-6). Patients had a mean age of 41.5 years (range: 18 to 65 years), 85% were women, and 95% were white. Thirty-six percent of patients were taking concomitant preventive medication for migraine. The mean number of migraine days per 28-day period in the 3 months preceding screening was 14.1 days. There were 128 enrolled and treated patients in this study. In total, 100 patients (78.1%) completed the study (Week 104). Overall, the results of this open-label clinical study demonstrated that VYEPTI 300 mg administered by IV infusions every 12 weeks for the preventive treatment of migraine was associated with a sustained and clinically meaningful therapeutic effect, demonstrated by reductions in headache impact, improvements in measures of health-related quality of life, and overall improvement in global impressions of change in migraine over 2 years of treatment in adults with chronic migraine. The safety profile was consistent with the safety profiles observed in randomized, placebo-controlled studies with VYEPTI.
Headache impact and health related Quality of Life: The impact of migraine headache was assessed via Headache Impact Test (HIT-6) and Short Form health survey (SF-36v2), respectively, in PROMISE-2 and PREVAIL.
In PROMISE-2, at baseline patients were severely impacted, with a mean total score of 65. At week 12, patients treated with eptinezumab showed a statistically significant improvement in the HIT-6 total score versus placebo compared to baseline. The change from baseline to week 12 in the VYEPTI treatment groups was clinically meaningful: the mean change from baseline to week 12 was -6.2 (p=0.0010) for eptinezumab 100 mg, -7.3 (p<0.0001) for 300 mg, and -4.5 for placebo. The improvements were sustained over the entire treatment period and up to the safety follow-up, 20 weeks after the last infusion administration.
In the long-term study, PREVAIL, at baseline patients were severely impacted with a mean total HIT-6 of 65. The mean change from baseline through week 104 was -9.7 (p<0.0001).
In PROMISE-2, patients treated with VYEPTI showed a significant and clinically meaningful improvement in physical (PCS) and mental (MCS) component summary scores of the SF-36v2 from baseline to Week 12 compared to placebo. The mean change from baseline to week 12 in MCS was 2.78 for 100 mg (p = 0.0009), 2.78 for 300 mg (p = 0.0010), and 0.93 for placebo. The mean change from baseline to week 12 in PCS was 3.79 for 100 mg (p= 0.07), 4.86 for 300 mg (p < 0.0001), and 3.03 for placebo.
In the long-term study, PREVAIL, patients treated with VYEPTI showed clinically meaningful improvements in the physical and mental component summary scores of the SF-36v2: the mean change from baseline in MCS (baseline 51.3) was 3 (p=0.0045), and in PCS (baseline 46.7) was 4.3 (p<0.0001).
Improvement in health-related quality of life and physical function was maintained in both studies through the entire study duration of 24 weeks and 104 weeks, respectively.
Pharmacokinetics: As eptinezumab is administered intravenously, it is 100% bioavailable. Eptinezumab exhibits linear pharmacokinetics and exposure increases proportionally with doses from 1 to 1000 mg. Steady-state is attained after the first-dose during a once every 12 weeks dosing schedule. Median time to maximum concentration (Cmax) is 30 minutes (end-of-infusion), and the average terminal elimination half-life is 27 days. The mean accumulation ratios based on Cmax and AUC0-tau are 1.08 and 1.15, respectively.
Absorption: VYEPTI is administered by intravenous infusion which bypasses extravascular absorption and is 100% bioavailable. Median time to peak concentration was attained at the end of infusion (30 minutes).
Distribution: The central volume of distribution (Vc) for eptinezumab was approximately 3.7 liters.
Biotransformation: Eptinezumab is expected to be degraded by proteolytic enzymes into small peptides and amino acids.
Elimination: Eptinezumab apparent clearance was 0.15 L/day, and the terminal elimination half-life was approximately 27 days.
Special populations: The pharmacokinetics of eptinezumab were not affected by age, gender, or race based on population pharmacokinetics. Therefore, no dose adjustment is needed.
A population pharmacokinetic analysis including 2123 subjects explored the effect of age, gender, ethnicity and body weight on the pharmacokinetics of eptinezumab. Relative to a 70 kg subject, steady state exposure of eptinezumab in a 190 kg subject was up to 52% lower, whereas is would be up to 50% higher in a 39 kg subject. However, from the exposure-response evaluation, there was no effect of body weight on the clinical outcome. No dose adjustment is needed based on body weight.
Renal or Hepatic Impairment: No dedicated hepatic or renal impairment studies were conducted to assess the effects of hepatic and renal impairment upon the pharmacokinetics of eptinezumab. Population pharmacokinetic analysis of integrated data from the VYEPTI clinical studies did not reveal any differences in patients with renal or hepatic impairment that would require dose adjustment.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, juvenile toxicity, or toxicity to reproduction and development.
Safety pharmacology and general toxicology: Safety pharmacology and general toxicity assessments after intravenous (IV) administration of eptinezumab once every 2 weeks for 6 months in cynomolgus monkeys identified the no-observed-adverse-effect-level (NOAEL) as the highest dose tested (150 mg/kg/dose). This supports a 103-fold or 123-fold safety margin, respectively, by Cmax or AUC for the highest dose (300 mg) administered by IV infusion every 12 weeks in humans.
Genotoxicity and Carcinogenesis: As eptinezumab is unlikely to interact directly with DNA or other chromosomal material, evaluations for potential genotoxicity were considered unnecessary and not performed.
As no carcinogenicity risk has been identified by extensive evaluation of the literature related to inhibition of CGRP and as no eptinezumab-related proliferative findings were observed in long term studies in monkeys, carcinogenicity testing was considered unnecessary and not performed.
Reproductive and Developmental Toxicology: Eptinezumab administered by weekly IV at doses of 0, 75 or 150 mg/kg/dose showed no adverse effects on male or female fertility (rats), embryofetal development (rats and rabbits), postnatal survival, growth, or development during the pre- and postweaning period, including behavioral or reproductive performance (rats).
For all studies, the NOAEL was the highest dose tested (150 mg/kg) which is 35-fold higher than the highest recommended human dose, based on body weight.
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