Drug Monograph Drug Name: Orladeyo™ (Berotralstat) Capsule Drug Class: Plasma Kallikrein Inhibitor Prepared For: MO Healthnet Prepared By: Conduent

Drug Monograph Drug Name: Orladeyo™ (berotralstat) Capsule Drug Class: Plasma Kallikrein Inhibitor Prepared For: MO HealthNet Prepared By: Conduent

New Criteria Revision of Existing Criteria

Executive Summary

The purpose of this monograph is to provide a review of new therapy to determine whether the reviewed drug should be made available on an open Purpose: access basis to prescribers, require a clinical edit or require prior authorization for use.

Orladeyo is available as a 110 mg and 150 mg capsule. Dosage Forms:

Manufacturer: Manufactured for: BioCryst Pharmaceuticals, Inc. Durham, NC 27703.

The efficacy of Orladeyo was established in a Phase 3 randomized, double- blind, placebo-controlled trial of 96 participants with hereditary angioedema Type 1 or Type 2. Patients were randomized to receive either Orladeyo 110 mg, Orladeyo 150 mg or placebo once daily for 24 weeks. The primary Summary of endpoint was the rate of investigator-confirmed hereditary angioedema Findings: attacks during dosing in the entire 24-week treatment period. Both treatment groups showed statistically significant results for the primary endpoint. The Orladeyo 110 mg treatment group showed a 30% reduction in attack rate (p=0.024) and the 150 mg treatment group showed a 44.2% reduction in attack rate (p<0.001) as compared to placebo.

Status Clinical Edit PA Required Recommendation: Open Access PDL

Type of PA Appropriate Indications Non-Preferred Criteria: No PA Required Preferred

Purpose The purpose of this monograph is to provide a review of new therapy to determine whether the reviewed drug should be considered a prior authorization drug, a clinical edit drug or an open access drug. While prescription expenditures are increasing at double-digit rates, payers are evaluating ways to control these costs by influencing prescriber behavior and guide appropriate medication usage. This review will assist in the achievement of qualitative and economic goals related to health care resource utilization. Restricting the use of certain medications can reduce costs by requiring documentation of appropriate indications for use, and where appropriate, encourage the use of less expensive agents within a drug class.

Introduction (1,2) Hereditary angioedema (HAE) is a rare inherited autosomal dominant (on chromosome 11) disorder resulting in recurrent episodes of fluid accumulation outside the blood vessels, blocking the normal flow of blood or lymph, causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. The most common form of the disorder is HAE type I, which is the result of C1 esterase inhibitor complement protein deficiency. These complement proteins help regulate various body functions such as the flow of fluids in and out of cells. HAE type II occurs as the result of the production of abnormal C1 esterase inhibitor proteins. Symptoms of HAE may recur and can become more severe. Injury, severe pain, surgery, dental procedures, viral illness, and/or stress can trigger or worsen symptoms. Symptoms of the gastrointestinal system include nausea, vomiting, acute abdominal pain and/or other signs of obstruction. Swelling of the throat or larynx can result in pain, difficulty swallowing, difficulty speaking, noisy respiration, and life-threatening asphyxiation. Symptoms typically develop in early childhood. Untreated patients may suffer attacks as often as every few days. About 50% or patients have monthly exacerbations and another 40% have 6 to 11 attacks annually. It is estimated that 1 in 50,000 people is affected by HAE in the United States.

Dosage Form (3) Orladeyo is available as a 110 mg and 150 mg capsule.

Manufacturer (3) Manufactured for: BioCryst Pharmaceuticals, Inc. Durham, NC 27703.

Indication(s) (3) Orladeyo is indicated for prophylaxis to prevent attacks of hereditary angioedema in adults and pediatric patients 12 years and older. Clinical Efficacy (3,4,5) (mechanism of action/pharmacology, comparative efficacy) Orladeyo is a plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity. It decreases plasma kallikrein activity to control excess bradykinin production in patient with HAE. Bradykinin is a potent vasodilator that increases vascular permeability, resulting in the swelling and pain associated with HAE. Plasma kallikrein cleaves high-molecular-weight kininogen (HMWK) to produce cleaved HMWK (cHMWK) and bradykinin. In patients with HAE due to C1- inhibitor deficiency or dysfunction, normal regulation of plasma kallikrein is not present.

Pharmacokinetics: Absorption Tmax=5 hours (with food), 2 hours (fasted)

Metabolism Hepatic by CYP2D6 and CYP3A4 Excretion Urine=9%, Feces=79% Half-life 93 hours

Clinical Trials Experience STUDY DESIGN Phase 3, multicenter, randomized, double-blind, placebo-controlled (APeX-2) trial (n=96) INCLUSION  Clinical diagnosis of HAE Type 1 or Type 2 CRITERIA  Subject weight of ≥40 kg  Access to and ability to use one or more acute medications approved by the relevant competent authority for the treatment of acute attacks of HAE  Must be medically appropriate for on-demand treatment as the sole medicinal management for their HAE during the study  Must have a specified number of investigator confirmed attacks during the run-in period of a maximum of 56 days from the Screening visit  Acceptable effective contraception

EXCLUSION  Pregnancy or breast-feeding CRITERIA  Medical condition, history or abnormal laboratory value that would interfere with the subject’s safety or ability to participate in the study  Severe hypersensitivity to multiple medicinal products or severe hypersensitivity/anaphylaxis with unclear etiology  Use of C1-INH within 14 days or use of androgens or tranexamic acid within 28 days prior to the Screening visit for prophylaxis of HAE attacks, or initiation of these drugs during the study TREATMENT Patients were randomized to Orladeyo 110 mg, Orladeyo 150 mg or REGIMEN placebo once daily with food for 24 weeks. RESULTS The primary endpoint was the rate of investigator-confirmed HAE attacks during dosing in the entire 24-week treatment period (Day 1 to Day 168).

The primary endpoint analysis demonstrated a statistically significant reduction the HAE attack rates in the 110 mg daily and the 150 mg treatment group compared to placebo.  Orladeyo 110 mg daily (n=41): HAE attack rate 1.65, 30% reduction (p=0.024)  Orladeyo 150 mg daily (n=40): HAE attack rate 1.31, 44.2% reduction (p<0.001)  Placebo (n=40): HAE attack rate 2.35

SAFETY Discussed in the Adverse Effects section below.

Contraindications (3,4)  None

Warnings and Precautions (3,4)  An increase in QT prolongation can occur at dosages higher than the recommended 150 mg once daily dosage. Additional doses or doses of Orladeyo higher than 150mg once daily are not recommended.  There are insufficient data in pregnant women available to inform drug-related risks with Orladeyo use in pregnancy.  There are no data on the presence of Orladeyo in human milk, its effects on the breastfed infant, or if effects on milk production. Adverse Effects (3)

Orladeyo Placebo 110 mg 150 mg Total Most common, ≥10% (n=39) (n=41) (n=40) (n=81) n (%) n (%) n (%) n (%) Abdominal pain 4 (10) 4 (10) 9 (23) 13 (16) Vomiting 1 (3) 4 (10) 6 (15) 10 (12) Diarrhea 0 4 (10) 6 (15) 10 (12) Back pain 1 (3) 1 (2) 4 (10) 5 (6) Gastroesophageal Reflux 0 4 (10) 2 (5) 6 (7) Disease

Drug Interactions (3,4)  P-gp or BCRP inhibitors: Orladeyo is a P-gp and BCRP substrate. A dose of 110 mg Orladeyo is recommended for patients with chronic administration of P-gp or BCRP inhibitors (e.g., cyclosporine).  P-gp inducers: may decrease Orladeyo plasma concentration, leading to reduced efficacy of Orladeyo. The use of P-gp inducers (e.g., rifampin, St. John’s wort) is not recommended with Orladeyo.  P-gp substrates: Orladeyo at a dose of 300 mg is a P-gp inhibitor. Appropriate monitoring and dose titration is recommended for P-gp substrates (e.g., digoxin) when co-administering with Orladeyo.  CYP2D6 and CYP3A4 substrates: Orladeyo at a dose of 150 mg is a moderate inhibitor of CYP2D6 and CYP3A4. For concomitant medications with a narrow therapeutic index that are predominantly metabolized by CYP2D6 (e.g., thioridazine, pimozide) or CYP3A4 (e.g., cyclosporine, fentanyl), appropriate monitoring and dose titration is recommended.

Dosage and Administration (3,4)  150 mg orally once daily  110 mg orally once daily in patients with moderate to severe hepatic impairment (Child- Pugh Class B or C), concomitant use of P-gp or BCRP inhibitors, or patients with persistent gastrointestinal reactions on 150mg dose.

Cost

Generic Name Brand Name Manufacturer Dose Cost**/ Month Berotralstat Orladeyo BioCryst 150 mg cap orally $37,308 Pharmaceuticals once daily C1 esterase Haegarda CSL Behring 60 units/kg SubQ $39,889.76 inhibitor twice weekly Lanadelumab Takhzyro Dyax Corp/Shire 300mg SubQ every $45,464.20 2 weeks C1 esterase Berinert CSL Behring 20 units/kg IV $9,750/kit inhibitor (treatment) C1 esterase Cinryze Shire 1,000 units IV with $5,517.58/1,000 inhibitor additional 1,000 units units in 60 minutes if needed Icatibant Firazyr Shire 30mg SubQ once, $5,083.26/30mg may repeat in 6 hours if needed Ecallantide Kalbitor Dyax Corp/Shire 30mg SubQ as 3 $14,767.63/30mg injections, may give an additional dose in 24 hour period C1 esterase Ruconest Bausch Health 50 units/kg/dose $12,468/dose inhibitor SIVP over 5 minutes, may give an additional dose in 24 hours period ** Wholesale Acquisition Cost

Conclusion Hereditary angioedema is a rare genetic disorder characterized by recurring attacks of edema in various parts of the body, including the face, hands, feet, airways and gastrointestinal tract. It is caused by mutations in the gene that codes for the complement protein, C1 esterase inhibitor. Medications for HAE can be grouped into on-demand therapies taken during acute attacks and prophylactic therapies. Orladeyo is a plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity. It decreases plasma kallikrein activity to control excess bradykinin production in patient with HAE. It is indicated for prophylaxis to prevent attacks of hereditary angioedema in adults and pediatric patients 12 years and older. The efficacy of Orladeyo was established in a Phase 3 randomized, double-blind, placebo-controlled trial of 96 participants with hereditary angioedema Type 1 or Type 2. The primary endpoint was the rate of investigator- confirmed hereditary angioedema attacks during dosing in the entire 24-week treatment period. The Orladeyo 110 mg treatment group showed a 30% reduction in attack rate (p=0.024) and the 150 mg treatment group showed a 44.2% reduction in attack rate (p<0.001) as compared to placebo. The most common adverse events associated with Orladeyo were abdominal pain, vomiting, diarrhea, back pain, and gastroesophageal reflux disease.

Recommendation This drug is being considered for inclusion in the state specific Preferred Drug List (PDL) as non-preferred. References 1) Hereditary Angioedema. National Organization for Rare Disorders. https://rarediseases.org/rarediseases/hereditary-angioedema/. 2008. 2) Orladeyo New Drug Review. IPD Analytics. https://secure.ipdanalytics.com/User/Pharma/RxStrategy/Search?q=Orladeyo. December 2020. 3) Orladeyo Package Insert. https://biocryst.com/wp- content/uploads/2020/12/ORLADEYO_PI_V1_2020.pdf. December 2020. 4) Clinical Pharmacology. https://www.clinicalkey.com/pharmacology/monograph/5294?n=Orladeyo. Accessed December 24, 2020. 5) U.S. National Library of Medicine. Efficacy and Safety of BCX7353 as an Oral Treatment for the Prevention of Attacks in HAE (APeX-2). https://clinicaltrials.gov/ct2/show/NCT03485911?term=NCT03485911&draw=2&rank=1. Accessed December 24, 2020.

Prepared by: April Ash, PharmD Date: January 15, 2021