Pagenax

Brolucizumab.

Brolucizumab is a humanized monoclonal single-chain Fv (scFv) antibody fragment with a molecular weight of ~26 kDa, produced in Escherichia coli cells by recombinant DNA technology.
One mL solution for injection contains 120 mg of brolucizumab.
Each vial contains 27.6 mg of brolucizumab in 0.23 mL solution. This provides a usable amount to deliver a single dose of 0.05 mL containing 6 mg of brolucizumab.
Excipients/Inactive Ingredients: 10 mM sodium citrate, 5.8% sucrose, 0.02% polysorbate 80 and water for injection and has a pH of approximately 7.2.

Pharmacotherapeutic group: Ophthalmologicals, Antineovascularization agents. ATC code: S01LA06.
Pharmacology: Mechanism of action (MOA): Increased levels of signaling through the vascular endothelial growth factor A (VEGF-A) pathway are associated with pathologic ocular angiogenesis and retinal edema. Brolucizumab binds with high affinity to VEGF-A isoforms (e.g. VEGF₁₁₀, VEGF₁₂₁, and VEGF₁₆₅), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A binding, brolucizumab suppresses endothelial cell proliferation, thereby reducing pathologic neovascularization and decreasing vascular permeability.
Pharmacodynamics (PD): Neovascular (wet) age-related macular degeneration (AMD) is characterized by pathological choroidal neovascularization (CNV). Leakage of blood and fluid from CNV may cause retinal thickening or edema and/or sub/intra-retinal hemorrhage, resulting in loss of visual acuity.
In the HAWK and HARRIER studies, related anatomical parameters were part of the disease activity assessments guiding treatment decisions. Reductions in central subfield thickness (CST) and in presence of intraretinal/subretinal fluid (IRF/SRF) or sub-retinal pigment epithelium (sub-RPE) fluid were observed in patients treated with Pagenax as early as 4 weeks after treatment initiation and up to Week 48 and Week 96. Statistically significant greater reductions in CST and in presence of IRF/SRF relative to aflibercept were demonstrated at Weeks 16 and 48 (see Clinical studies as follows).
In these studies, for patients treated with Pagenax, reductions in CNV lesion size were observed as early as 12 weeks, and at Weeks 48 and 96 after treatment initiation.
Clinical studies: The safety and efficacy of Pagenax were assessed in two randomized, multi-center, double-masked, active-controlled Phase III studies (HAWK and HARRIER) in patients with neovascular (wet) AMD. A total of 1,817 patients were treated in these studies for two years (1,088 on Pagenax and 729 on aflibercept). Patient ages ranged from 50 to 97 years with a mean age of 76 years.
In HAWK, patients were randomized in a 1:1:1 ratio to the following dosing regimens: Pagenax 3 mg administered every 12 or 8 weeks (q12w/q8w) after the first 3 monthly doses, Pagenax 6 mg administered every 12 or 8 weeks (q12w/q8w) after the first 3 monthly doses, aflibercept 2 mg administered every 8 weeks (q8w) after the first 3 monthly doses.
In HARRIER, patients were randomized in a 1:1 ratio to the following dosing regimens: Pagenax 6 mg administered every 12 or 8 weeks (q12w/q8w) after the first 3 monthly doses, aflibercept 2 mg administered every 8 weeks (q8w) after the first 3 monthly doses.
In both studies, after the first three monthly doses (Week 0, 4 and 8), brolucizumab patients were treated q12w, with the option of adjusting to q8w dosing interval based on disease activity. Disease activity was assessed by a physician during the first q12 week interval (at Week 16 and 20) and at each subsequent scheduled q12w treatment visit. Patients who showed disease activity (e.g. decreased visual acuity, increased central subfield thickness (CST), and/or presence of retinal fluids (IRF/SRF, sub-RPE)) at any of these visits were adjusted to a q8w treatment interval.
Results: The primary efficacy endpoint for the studies was the change from baseline in Best Corrected Visual Acuity (BCVA) to Week 48 as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score with the primary objective to demonstrate non-inferiority of Pagenax vs. aflibercept. In both studies, Pagenax (administered in a q12w/q8w regimen) demonstrated non-inferior efficacy to aflibercept 2 mg (administered q8w). The visual acuity gains observed in the first year were maintained in the second year.
Detailed results of both studies are shown in Table 1 and Figure 1 as follows. (See Table 1 and Figure 1.)


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These visual acuity gains were achieved with 56% and 51% patients treated with Pagenax 6 mg on q12w dosing interval at Week 48, and with 45% and 39% of patients at Week 96 in HAWK and HARRIER, respectively. Among patients identified as eligible for q12w interval during the first 12 week interval, 85% and 82% remained on the q12w dosing interval up to Week 48. Of patients on the q12w interval at Week 48, 82% and 75% remained on the 12 week dosing interval through Week 96.
Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity, baseline retinal thickness, lesion type, lesion size, fluid status) in each study were generally consistent with the results in the overall population.
Disease activity was assessed by changes in visual acuity and/or anatomical parameters, including central subfield thickness (CST) and/or presence of retinal fluids (IRF/SRF, sub-RPE). At Week 16, when disease activity was first assessed for determining the treatment interval, statistically fewer patients showed disease activity on Pagenax 6 mg compared to aflibercept 2 mg. Disease activity was assessed throughout the studies. Anatomical parameters of disease activity were decreased at Week 48 and at Week 96 for Pagenax compared to aflibercept (Table 2). (See Table 2 and Figure 2.)


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In both studies, Pagenax demonstrated clinically meaningful increases from baseline in the pre-specified secondary efficacy endpoint of patient reported outcomes, reported through the National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA). Patient reported outcomes benefits were maintained in the second year.
No clinically meaningful differences were found between Pagenax and aflibercept in changes from baseline to Week 48 in NEI VFQ-25 total score and subscales (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, and peripheral vision).
Pharmacokinetics (PK): Pagenax is administered directly into the vitreous to exert local effects in the eye.
Absorption/Distribution: After intravitreal administration of 6 mg brolucizumab per eye to patients with nAMD, the mean C_max of free brolucizumab in the plasma was 49.0 ng/mL (range: 8.97 to 548 ng/mL) and was attained in 1 day.
Metabolism/Elimination: Brolucizumab is a monoclonal antibody fragment and no drug metabolism studies have been conducted. As a single-chain antibody fragment, free brolucizumab is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF, passive renal elimination, and metabolism via proteolysis.
After intravitreal injections, brolucizumab was eliminated with an apparent systemic half-life of 4.3 days. Concentrations were generally near or below the quantitation limit (<0.5 ng/mL) approximately 4 weeks after dosing in most patients. Pagenax did not accumulate in the serum when administered intravitreally every 4 weeks.
Special populations: Geriatric patients (65 years or above): In the HAWK and HARRIER clinical studies, approximately 90% (978/1088) of patients randomized to treatment with Pagenax were ≥65 years of age and approximately 60% (648/1088) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies.
Race/Ethnicity: There were no ethnic differences in systemic pharmacokinetics following intravitreal injection in a study with 24 Caucasian and 26 Japanese patients.
Renal impairment: Mild to severe renal impairment should have no impact on the overall systemic exposure to brolucizumab, because the systemic concentration of brolucizumab is driven by the distribution from the eye rather than the elimination rate and because the systemic exposure of free brolucizumab is low.
The systemic clearance of brolucizumab was evaluated in nAMD patients who had both serum brolucizumab pharmacokinetic and creatinine clearance data available. Subjects with mild (50 to 79 mL/min (n=13)) renal impairment had mean systemic clearance rates of brolucizumab which were within 15% of the mean clearance rate for subjects with normal renal function (≥80 mL/min (n=25)). Patients with moderate (30 to 49 mL/min (n=3)) renal impairment had mean systemic clearance rates of brolucizumab which were lower than patients with normal renal function but the number of patients was too low to make definitive conclusions. No patients with severe (<30 mL/min) renal impairment were studied.
Hepatic impairment: Mild to severe hepatic impairment should have no impact on the overall systemic exposure to brolucizumab, because metabolism occurs via proteolysis and does not depend on hepatic function.
Toxicology: Non-clinical safety data: Carcinogenicity and mutagenicity: No studies have been conducted on the carcinogenic or mutagenic potential of Pagenax.
Repeat dose toxicity: Non-clinical data reveal no special hazard for humans based on 3- and 6-month repeated dose toxicity studies. Intravitreal injections of brolucizumab to cynomolgus monkeys at doses up to 6 mg per eye every 4 weeks for 26 weeks resulted in no ocular or systemic effects and were well-tolerated.
Evaluations included daily observations for morbidity and mortality, clinical observations (including abnormal respiration and behavior), body weight determinations, biomicroscopic and indirect ophthalmoscopic examinations, intraocular pressure measurements, electroretinograms, clinical pathology, toxicokinetic and anti-drug antibody analysis of the serum and vitreous, and macroscopic and microscopic examinations.
The ocular and systemic no observed adverse effect level (NOAEL) with brolucizumab 6 mg per eye every 4 weeks provides a 2-fold margin of ocular safety (based on comparative ocular volume) for the recommended human dose.

Pagenax is indicated for the treatment of neovascular (wet) age-related macular degeneration (AMD).

Dosage regimen: Single-use vial for intravitreal use only. Each vial should only be used for the treatment of a single eye.
Pagenax must be administered by a qualified physician.
General target population: The recommended dose for Pagenax is 6 mg (0.05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first three doses. Thereafter, Pagenax is administered every 12 weeks (3 months). The physician may individualize treatment intervals based on disease activity as assessed by visual acuity and/or anatomical parameters. The treatment interval could be as frequent as every 8 weeks (2 months) (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Special populations: Renal impairment: No dosage regimen adjustment is required in patients with renal impairment (see Pharmacology under Actions).
Hepatic impairment: No dosage regimen adjustment is required in patients with hepatic impairment (see Pharmacology under Actions).
Pediatric patients (below 18 years): The safety and efficacy of Pagenax in pediatric patients have not been established.
Geriatric patients (65 years or above): No dosage regimen adjustment is required in patients 65 years or above.
Method of administration: As with all medicinal products for intravitreal use, Pagenax should be inspected visually prior to administration (see Instructions for use under Patient Counselling Information).
The injection procedure must be carried out under aseptic conditions, which include the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent). Sterile paracentesis equipment should be available as a precautionary measure. Patient's medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see Contraindications). Adequate anesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection.
For information on preparation of Pagenax, see Instructions for use under Patient Counselling Information.
The injection needle should be inserted 3.5 to 4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the center of the globe. The injection volume of 0.05 mL is then delivered slowly; a different scleral site should be used for subsequent injections.
The safety and efficacy of Pagenax administered to both eyes concurrently have not been studied.

Overdosing with greater than recommended injection volume may increase intraocular pressure. Therefore, in case of overdose, intraocular pressure should be monitored and if deemed necessary by the treating physician, appropriate treatment should be initiated.

Hypersensitivity to the active substance or to any of the excipients.
Active or suspected ocular or periocular infection.
Active intraocular inflammation.

Endophthalmitis, retinal detachment, retinal vasculitis and/or retinal vascular occlusion: Intravitreal injections, including those with Pagenax, have been associated with endophthalmitis and retinal detachment. Proper aseptic injection techniques must always be used when administering Pagenax.
Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of Pagenax (see Contraindications and Adverse Reactions).
Patients should be instructed to report any symptoms suggestive of the above mentioned events without delay.
Intraocular pressure increases: Transient increases in intraocular pressure have been seen within 30 minutes of injection, similar to those observed with intravitreal administration of other VEGF inhibitors (see Adverse Reactions). Sustained intraocular pressure increases have also been reported with Pagenax. Special precaution is needed in patients with poorly controlled glaucoma (do not inject Pagenax while the intraocular pressure is ≥30 mmHg). Both intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately.
Bilateral treatment: The safety and efficacy of brolucizumab administered in both eyes concurrently have not been studied.
Immunogenicity: As this is a therapeutic protein, there is a potential immunogenicity with brolucizumab (see Adverse Reactions). Patients should be instructed to inform their physician if they develop symptoms such as eye pain or increased discomfort, worsening eye redness, blurred or decreased vision, an increased number of small particles in their vision, or increased sensitivity to light (see Adverse Reactions).
Concomitant use of other anti-VEGF: There are no data available on the concomitant use of Pagenax with other anti-VEGF medicinal products in the same eye. Brolucizumab should not be administered concurrently with other anti-VEGF medicinal products (systemic or ocular).
Withholding treatment: In intravitreal anti-VEGF treatments, the dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of: a decreased in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity; a retinal break; a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50% of the total lesion area; performed or planned intraocular surgery within the previous or next 28 days.
Retinal pigment epithelial tear: Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for wet AMD include a large and/or high pigment epithelial retinal detachment. When initiating brolucizumab therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.
Rhegmatogenous retinal detachment or macular holes: Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.
Systemic effects following intravitreal use: Systemic adverse events, including non-ocular haemorrhages and arterial thromboembolic events, have been reported following intravitreal injection of VEGF inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. There are limited data on safety in the treatment of patients with AMD with a history of stroke, transient ischaemic attacks or myocardial infarction within the last 3 months. Caution should be exercised when treating such patients.
Driving and using machines: Patients may experience temporary visual disturbances after an intravitreal injection with Pagenax and the associated eye examination, and should therefore be advised not to drive or use machinery until visual function has recovered sufficiently.

Pregnancy: Risk summary: There are no adequate and well-controlled studies of Pagenax administration in pregnant women and no animal reproduction studies have been conducted. The potential risk of use of Pagenax in pregnancy is unknown. A study in pregnant cynomolgus monkeys did not indicate any harmful effects with the respect to pre- or postnatal development at approximately 6-times the human exposure based on serum C_max (see Animal data as follows). However, based on the anti-VEGF mechanism of action, brolucizumab must be regarded as potentially teratogenic and embryo/fetotoxic. Therefore, Pagenax should not be used during pregnancy unless the expected benefits outweigh the potential risks to the fetus.
Animal data: No reproductive or fertility studies have been conducted. In an enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus monkeys, brolucizumab was administered to all animals by intravitreal (IVT) injection to one eye at doses of 3 or 6 mg once every 4 weeks until delivery. One additional injection was administered to a subset of animals 28 days post-partum and had a milk collected for tocixokinetic evaluations. There was no impact of IVT administration of brolucizumab on embryo-fetal development, pregnancy or parturitition; or on the survival, growth, or postnatal development of offspring. This represents an exposure approximately 6-times the human exposure (based on serum Cmax) at the proposed clinical dose of 6 mg. However, VEGF inhibition has been shown to affect follicular development, corpus luteum function, and fertility. Based on the mechanism of action of VEGF inhibitors, there is a potential risk to female reproduction and to embryo-fetal development.
Lactation: It is unknown if brolucizumab is transferred into human milk after administration of Pagenax. There are no data on the effects of Pagenax on the breastfed child or on milk production. In an ePPND study, brolucizumab was not detected in the maternal milk or infant serum of cynomolgus monkeys. Because of the potential for adverse drug reactions in the breastfed child, breastfeeding is not recommended during treatment and for at least one month after the last dose when stopping treatment with Pagenax.
Females of reproductive potential: Females of reproductive potential should use effective contraception (methods that result in less than 1 % pregnancy rates) during treatment with Pagenax and for at least one month after the last dose when stopping treatment with Pagenax.

A total of 1088 patients treated with Pagenax constituted the safety population in the two Phase III studies HAWK and HARRIER with a cumulative 96 weeks exposure to Pagenax and 730 patients treated with the recommended dose of 6 mg.
The most frequently reported adverse drug reactions in >5% of patients treated with Pagenax 6 mg were visual acuity reduced (7.3%), cataract (7.0%), conjunctival haemorrhage (6.3%), and vitreous floaters (5.1%).
Less common serious adverse drug reactions reported in <1% of the patients treated with Pagenax 6 mg were endophthalmitis, blindness, retinal artery occlusion and retinal detachment.
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions from clinical trials (Table 3) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 3.)


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Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse drug reactions have been derived from post-marketing experience with Pagenax via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. (See Table 4.)


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Immunogenicity: As with all therapeutic proteins, there is a potential for an immune response in patients treated with Pagenax. The immunogenicity of Pagenax was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to Pagenax in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Pagenax with the incidence of antibodies to other products may be misleading.
Pre-treatment antibodies have been detected in drug-naïve subjects for a variety of biotechnology-derived therapeutic proteins including single-chain antibodies. The pre-treatment incidence of anti-brolucizumab antibodies was 35 - 52%. After dosing with Pagenax for 88 weeks, treatment-emergent anti-brolucizumab antibodies were detected in 23 - 25% of patients.
Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy. Among patients with treatment-emergent antibodies, a higher number of intraocular inflammation events were observed. The clinical significance of anti-brolucizumab antibodies on safety is unclear at this time.
Product-class-related adverse reactions: There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. A low incidence rate of arterial thromboembolic events was observed in the brolucizumab clinical studies in patients with AMD. There were no major notable differences between the groups treated with brolucizumab and comparator.

No formal interaction studies have been performed.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Vial: Store in a refrigerator at 2°C to 8°C.
Prior to use, the unopened vial may be kept at room temperature (not more than 30°C) for up to 24 hours.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.

Instructions for use of the Pagenax vial kit: Storage and inspection: Store Pagenax in the refrigerator (2°C to 8°C/36°F to 46°F); do not freeze. Keep the vial in the outer carton to protect from light.
Prior to use, the unopened vial of Pagenax may be kept at room temperature (below 25°C/77°F) for up to 24 hours. After opening the vial, proceed under aseptic conditions.
Pagenax is a clear to slightly opalescent and colorless to slightly brownish-yellow solution.
The solution should be inspected visually upon removal from the refrigerator and prior to administration. If particulates or cloudiness are visible, the vial must not be used and appropriate replacement procedures followed.
The contents of the vial and filter needle are sterile and for single use only. Do not use if the packaging, vial and/or filter needle are damaged or expired.
How to prepare and administer Pagenax: The intravitreal injection procedure must be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent) and the availability of sterile paracentesis equipment (if required). Adequate anesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection.
For preparation and intravitreal injection the following single use medical devices are needed: A 30G x ½" injection needle, sterile.
A 1 mL syringe with a 0.05 mL dose mark, sterile.
The 5 μm blunt filter needle (18G x 1½", 1.2 mm x 40 mm), sterile.
The injection needle and the syringe are not included in the Pagenax vial kit.
Note: The dose must be set to 0.05 mL.
Ensure that the injection is given immediately after preparation of the dose (Step 8).
Injection procedure: 1. Remove the vial cap and clean the vial septum (e.g. with 70% alcohol swab).
2. Assemble the filter needle onto a 1 mL syringe using aseptic technique.
3. Push the filter needle into the center of the vial septum until the needle touches the bottom of the vial.
4. To withdraw the liquid, hold the vial slightly inclined and slowly withdraw all the liquid from the vial and filter needle.
Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
5. Disconnect the filter needle from the syringe in an aseptic manner and dispose of it.
The filter needle is not to be used for intravitreal injection.
6. Aseptically and firmly assemble a 30G x ½" injection needle onto the syringe.
7. To check for air bubbles, hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top.
8. Carefully expel the air from the syringe and adjust the dose to the 0.05 mL mark. The syringe is ready for the injection.
9. Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05 mL. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel.
Note: Any unused medicinal product or waste material should be disposed of in accordance with local regulations.

Other Eye Preparations

S01LA06 - brolucizumab ; Belongs to the class antineovasculatisation agents. Used in the management of neovascular macular degeneration.

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