Takhzyro for Hereditary Angioedema

On August 23, 2018, the FDA approved lanadelumab-flyo (Takhzyro; Shire) for the prophylaxis treatment and prevention of hereditary angioedema (HAE) in patients 12 years or older. Lanadelumab-flyo calls for less frequent dosages relative to current treatment options of once or twice monthly and is poised to reduce acute attack treatment utilization.

DISEASE

HAE is a rare genetic disorder characterized by repeated extreme swelling of the arms, face, feet, hands, gastrointestinal tract, and upper airways. It can be a debilitating disease that negatively affects work, school, and travel. Airway swelling and respiratory obstruction associated with HAE are potentially life-threatening due to asphyxiation. Associated HAE gastrointestinal tract swelling cases present as severe abdominal pain, nausea, and vomiting.

Occurring in approximately 1 in 10,000 to 50,000 individuals, children have a 50% chance of genetically inheriting HAE; however, 25% of HAE cases are linked to spontaneous genetic mutations. There are 3 types of HAE, none of which respond to antihistamine or corticosteroid therapy. In types 1 and 2 HAE, patients have a genetic defect that results in the loss of C1-inhibitor control and produces characteristic swelling. Type 1 HAE is characterized by low C1-inhibitor levels due to gene defects on chromosome 11. Type 2 HAE is characterized by normal to low C1-inhibitor levels, and the inhibitors that are present are dysfunctional. Type 3 HAE research is ongoing, but the type has been found to be characterized by normal C1-inhibitor levels and function.

MECHANISM OF ACTION

Lanadelumab-flyo is a fully human recombinant nonplasma-derived monoclonal antibody created in recombinant Chinese hamster ovary cells, and it inhibits plasma kallikrein. Plasma kallikrein is a protease that splits high-molecular—weight kininogen to produce a cleaved high-molecular–weight kininogen and bradykinin. The inhibition of plasma kallikrein reduces excess bradykinin production in patients with HAE. Bradykinin acts as a vasodilator that increases vascular permeability, leading to the characteristic HAE swelling and pain.

PHARMACOLOGY AND PHARMACOKINETICS

Lanadelumab-flyo provides concentration-dependent inhibition of plasma kallikrein and is dose proportional in the therapeutic dose range after subcutaneous (SC) administration. The elimination half-life is reached in 14 days, with peak plasma concentrations achieved at 5 days. The steady state concentrations are achieved at 70 days, with mean accumulation ratios of approximately 1.44, 1.42, and 2.43 for study dosing regimens of 150 mg every 4 weeks, 300 mg every 4 weeks, and 300 mg every 2 weeks, respectively. No significant or clinically meaningful differences were found during population pharmacokinetic analyses of age, gender and race. Clearance and volume of distribution fluctuated according to body weight; however, the differences were not clinically significant. Dosage adjustments were not recommended based on age, gender, race, or body weight. The coadministration of HAE acute attack rescue medications, plasma-derived and recombinant C1-INH, showed no changes in clearance and volume of distribution.

DOSAGE AND ADMINISTRATION

Lanadelumab-flyo’s suggested starting dose is 300 mg every 2 weeks. In well-controlled or attack-free patients, for at least 6 months, an extended dosing interval of 300 mg every 4 weeks may be more appropriate for some patients. No dosage adjustments are required for renal impairment.

Lanadelumab-flyo is available as a 300-mg/2 mL (150 mg/mL) single-dose vial solution, which should appear clear, slightly opalescent, colorless, or slightly yellow. No additional reconstitution, preparation, or dilution is necessary. The vial should not be used if the solution appears discolored or has visible particles, and the vial temperature should be allowed to normalize to room temperature prior to SC injection. Prescribing information recommends the drug be administered within 2 hours of dose syringe preparation. If refrigerated, it must be used within 8 hours of the dose syringe preparation.

For SC administration only, lanadelumab-flyo should be self-administered or administered by a caregiver. The prescribed dosage should be withdrawn from the vial using an 18-gauge needle and syringe. Using aseptic procedure, the needle should be changed to a 27-gauge, half-inch needle for SC administration into the abdomen, thigh, or upper arm. Unused portions of the drug remaining in the vial should be discarded after administration of the prescribed dose.

PLACE IN THERAPY

With a longer half-life than current prophylactic HAE treatments, lanadelumab-flyo data have been shown to reduce HAE attack incidence for longer intervals. It offers less frequent dosages relative to current treatments of every 2 or 4 weeks and is poised to reduce acute attack treatment utilization. Dosing intervals will be based on individual patient history, severity and frequency of attacks, and prescriber comfort level related to extending the dosing interval. Existing treatments require more frequent administration, which includes self-administered injectables for acute attacks or biweekly short acting intravenous infusions.

Reduced HAE attacks improve patient quality of life and the medication management burden. Lanadelumab-flyo should be used as a long-acting prophylaxis HAE treatment, while existing medications should be reserved for acute attack on-demand treatment.

“The data on lanadelumab continue to demonstrate the importance of controlling plasma kallikrein activity, which is chronically uncontrolled in those living with HAE, even between attacks,” Marc Riedl, MD, said in a Shire press release.

COST CONSIDERATIONS

Existing HAE treatments are costly and present financial challenges for payers. According to a recent study by Prime Therapeutics, the average yearly total cost of care was $409,925 per person. Ninety-seven percent ($395,507) of these costs are due to medications. The study reviewed emergency department visits, hospital visits, medication use, and total cost of care data. For patients treated with mul- tiple HAE medications, the average cost was more than $1 million per person. Treatment of multiple family members with HAE amplifies costs into the multimillions. However, lanadelumab-flyo is poised to reduce attack frequency and lower costly acute attack medication utilization. As a result, acute attack HAE drug utilization may be reduced.

Given the promising clinical efficacy data and reduced dosing intervals compared with existing treatments, lanadelumab-flyo is poised to be added to most pharmacy benefit manager (PBM) formularies. Average wholesale price data (AWP) are speculated to be $26,484 for each 2-mL vial, with an approximate annual cost of $688,584, excluding rebate or contractual PBM discounts. In comparison, the AWP for the complement C1 esterase inhibitor, Cinryze, is approximately $686,400 per year, while Haegarda has an annual AWP of $586,560, depending on weight-based dosing.

Competitor HAE prophylaxis products use rebates to offset the clinical advantages of lanadelumab-flyo. As market competition increases between prophylaxis products, PBM rebate values will increase within the drug class. Rebates or contractual PBM discounts are excluded from the above AWP costs.

CLINICAL STUDIES

The HELP study was a phase 3 international, randomized, multicenter, parallel-group, double-blind, placebo-controlled trial that lasted 26 weeks. As the largest HAE prevention study to date, the frequency of confirmed angioedema attack episodes in the lanadelumab versus placebo treatment groups was the primary efficacy endpoint. Study enrollment included type 1 or 2 HAE adult and adolescent patients 12 years or older (N = 125) who experienced 1 confirmed attack per month.

Randomized study enrollees were placed into 4 treatment groups: placebo, lanadelumab-flyo SC 300 mg every 2 weeks, lanadelumab-flyo SC 300 mg every 4 weeks, or lanadelumab-flyo SC 150 mg every 4 weeks. Patients in the lanadelumab-flyo treatment arms showed clinically meaningful and statistically significant drops in HAE attack rates. Compared with the placebo group, the 3 lanadelumab-flyo treatment arms reduced the number of HAE attacks by 76%, 73%, and 87%, respectively. Patients previously treated or currently taking C1 inhibitors were randomized into the placebo treatment group and the lanadelumab-flyo groups. Among the pretreated C1-inhibitor patients, the number of HAE attacks requiring acute treatment were reduced by 81%, 74%, and 87%, respectively, in the lanadelumab-flyo treatment arms.

As part of an uncontrolled, unblinded, open-label extension study, all patients who completed the HELP study were eligible to enroll and end points were investigative. The researchers administered 212 patients a starting dose of 300-mg lanadelumab-flyo. For patients previously treated in the 300-mg every 2 weeks dosing arm, results showed that 80% did not have an attack 4 weeks post dose.

WARNINGS AND PRECAUTIONS

According to the prescribing information, lanadelumab-flyo has no contraindications. The most common adverse effects include injection-site reactions (44%), upper respiratory infections (24%), headache (18%), rash (6%), myalgia (4%), dizziness (5%), and diarrhea (4%). Lanadelumab-flyo showed no effects on QT/QTc interval prolongation. Hypersensitivity reactions have been observed in lanadelumab-flyo.

About the Author

Genevieve Regal is Clinical Pharmacy Consultant for Confidio, a technology enabled pharmacy benefit consulting firm serving millions of members nationally. As a Confidio Clinical Consultant, Genevieve supports Health Plans, Employers, and PBMs in clinical strategies and formulary cost management. Genevieve Regal, PharmD, HC-MBA, received her Doctor of Pharmacy from the Philadelphia College of Pharmacy, University of the Sciences and graduated Summa Cum Laude from George Washington University with a Healthcare Master of Business Administration Degree. Genevieve has 13 years pharmacy leadership experience in Medicare Part D plan administration, quality improvement, CMS Compliance, Program Audits, Sanction Remediation, Part D Best Practices, MTM & Pharmacy Operations. For more information please visit: www.confidio.com or to reach the author, please email her at Genevieve.Regal@confidio.com