Pontevia

Galcanezumab.

Galcanezumab is a humanized IgG4 monoclonal antibody specific for calcitonin-gene related peptide (CGRP) ligand. Galcanezumab is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. Galcanezumab is composed of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains and has an overall molecular weight of approximately 147 kDa.
PONTEVIA (galcanezumab) injection is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow to slightly brown solution, for subcutaneous use. PONTEVIA is supplied in a 1 mL single-dose prefilled pen to deliver 120 mg of galcanezumab. Each mL of solution contains 120 mg of galcanezumab; L-histidine (0.5 mg); L- histidine hydrochloride monohydrate (1.5 mg); Polysorbate 80 (0.5 mg); Sodium Chloride (8.8 mg); Water for Injection, USP. The pH range is 5.3 - 6.3.

Pharmacology: Mechanism of Action: Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor.
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.)

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Figure 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.)

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Figure 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.)

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Chronic 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.)

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Study 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.)

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Figure 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.)

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Pharmacokinetics: 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 (C_{ave, 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 C_{ave, ss} 38 times that in humans at 120 mg.

Migraine: PONTEVIA is indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month.

Recommended Dosing for Migraine: The recommended dose is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.
Patients should be instructed to inject a missed dose as soon as possible and then resume monthly dosing.
The treatment benefit should be assessed within 3 months after initiation of treatment. Any further decision to continue treatment should be taken on an individual patient basis. Evaluation of the need to continue treatment is recommended regularly thereafter.
Elderly (≥65 years): There is limited information in subjects aged ≥65 years. No dose adjustment is required as the pharmacokinetics of galcanezumab are not affected by age.
Renal impairment/Hepatic impairment: No dose adjustment is required in patients with mild to moderate renal impairment or hepatic impairment.
Paediatric population: The safety and efficacy of galcanezumab in children aged 6 to 18 years have not yet been established. No data are available.
There is no relevant use of galcanezumab in children below the age of 6 years for the prevention of migraine.
Important Administration Instructions: PONTEVIA is for subcutaneous use only.
PONTEVIA is intended for patient self-administration. Prior to use, provide proper training to patients and/or caregivers on how to prepare and administer PONTEVIA using the single-dose prefilled pen, including aseptic technique [see Storage]: Protect PONTEVIA from direct sunlight.
Prior to subcutaneous administration, allow PONTEVIA to sit at room temperature for 30 minutes. Do not warm by using a heat source such as hot water or a microwave.
Do not shake the product.
Inspect PONTEVIA visually for particulate matter and discoloration prior to administration, whenever solution and container permit [see Storage]. Do not use PONTEVIA if it is cloudy or there are visible particles.
Administer PONTEVIA in the abdomen, thigh, back of the upper arm, or buttocks subcutaneously. Do not inject into areas where the skin is tender, bruised, red, or hard.
The prefilled pen is single-dose and deliver the entire contents.

Doses up to 600 mg have been administered subcutaneously to humans without dose-limiting toxicity. In case of an overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

PONTEVIA is contraindicated in patients with serious hypersensitivity to galcanezumab or to any of the excipients [see Hypersensitivity Reactions under Precautions].

Hypersensitivity Reactions: Serious hypersensitivity reactions including cases of anaphylaxis, angioedema and urticaria have been reported. If a serious hypersensitivity reaction occurs, administration of galcanezumab should be discontinued immediately and appropriate therapy initiated. [See Contraindications, Clinical Trials Experience under Adverse Reactions, and Patient Counselling Information].
Effects on ability to drive and use machines: Galcanezumab may have a minor influence on the ability to drive and use machines. Vertigo may occur following the administration of galcanezumab.

Pregnancy: Risk Summary: There are no adequate data on the developmental risk associated with the use of PONTEVIA in pregnant women. Administration of galcanezumab to rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation at plasma exposures greater than that expected clinically did not result in adverse effects on development (see Data: Animal Data as follows).
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. The estimated rate of major birth defects (2.2% - 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.
Clinical Considerations: Disease-Associated Maternal and/or Embryo/Fetal Risk: Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.
Data: Animal Data: 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 embryofetal development were observed. The highest dose tested (250 mg/kg) was associated with a plasma exposure (C_{ave, ss}) 38 times that in humans at the recommended human dose (RHD) for migraine (120 mg).
Administration of galcanezumab (0, 30, or 100 mg/kg) by subcutaneous injection to pregnant rabbits throughout the period of organogenesis produced no adverse effects on embryofetal development. The higher dose tested was associated with a plasma C_{ave, ss} 64 times that in humans at 120 mg.
Administration of galcanezumab (0, 30, or 250 mg/kg) by subcutaneous injection to rats throughout pregnancy and lactation produced no adverse effects on pre- and postnatal development. The higher dose tested was associated with a plasma C_{ave, ss} 34 times that in humans at 120 mg.
Lactation: Risk Summary: There are no data on the presence of galcanezumab in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PONTEVIA and any potential adverse effects on the breastfed infant from PONTEVIA or from the underlying maternal condition.

The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Hypersensitivity Reactions [see Contraindications and Hypersensitivity Reactions under Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.
Migraine: The safety of PONTEVIA has been evaluated in 2586 patients with migraine who received at least one dose of PONTEVIA, representing 1487 patient-years of exposure. Of these, 1920 patients were exposed to PONTEVIA once monthly for at least 6 months, and 526 patients were exposed for 12 months.
In placebo-controlled clinical studies (Studies 1, 2, and 3), 705 patients received at least one dose of PONTEVIA 120 mg once monthly, and 1451 patients received placebo, during 3 months or 6 months of double-blind treatment [see Pharmacology: Pharmacodynamics: Clinical Studies: Migraine under Actions]. Of the PONTEVIA-treated patients, approximately 85% were female, 77% were white, and the mean age was 41 years at study entry.
The most common adverse reaction was injection site reactions. In Studies 1, 2, and 3, 1.8% of patients discontinued double-blind treatment because of adverse events. Table 3 summarizes the adverse reactions that occurred within up to 6 months of treatment in the migraine studies. (See Table 3.)

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Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
For these reasons, comparison of the incidence of antibodies to galcanezumab in the studies described as follows with the incidence of antibodies in other studies or to other products may be misleading.
The immunogenicity of PONTEVIA has been evaluated using an in vitro immunoassay for the detection of binding anti-galcanezumab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro ligand-binding immunoassay was performed to detect neutralizing antibodies.
In controlled studies with PONTEVIA up to 6 months (Study 1, Study 2, and Study 3), the incidence of anti-galcanezumab antibody development was 4.8% (33/688) in patients receiving PONTEVIA once monthly (32 out of 33 of whom had in vitro neutralizing activity). With 12 months of treatment in an open-label study, up to 12.5% (16/128) of PONTEVIA-treated patients developed anti-galcanezumab antibodies, most of whom tested positive for neutralizing antibodies.
Although anti-galcanezumab antibody development was not found to affect the pharmacokinetics, safety or efficacy of PONTEVIA in these patients, the available data are too limited to make definitive conclusions.
Postmarketing Experience: The following adverse reactions have been identified during post-approval use of PONTEVIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to PONTEVIA exposure.
Immune System Disorders - Anaphylaxis, angioedema [see Contraindications and Hypersensitivity Reactions under Precautions].
Skin and Subcutaneous Tissue Disorders - rash, pruritus rash, urticaria.
Ear and Labyrinth disorders - vertigo.
Gastrointestinal disorders - constipation.

No drug interaction studies were conducted. No pharmacokinetic drug interactions are expected based on the characteristics of galcanezumab.

Store refrigerated at 2°C to 8°C in the original carton to protect PONTEVIA from light until use.
Do not freeze.
Do not shake.
PONTEVIA may be stored out of refrigeration in the original carton at temperatures up to 30°C for up to 7 days. Once stored out of refrigeration, do not place back in the refrigerator.
If these conditions are exceeded, PONTEVIA must be discarded.
Discard the PONTEVIA single-dose prefilled pen after use in a puncture-resistant container.

Instructions on Self-Administration: Provide guidance to patients and/or caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the prefilled pen correctly. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use PONTEVIA.
Serious Hypersensitivity Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reactions [see Hypersensitivity Reactions under Precautions].

Antimigraine Preparations

N02CD02 - galcanezumab ; Belongs to the class of calcitonin gene-related peptide (CGRP) antagonists preparations. Used to relieve migraine.

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