Clinical Policy: Ecallantide (Kalbitor) Reference Number: ERX.SPMN.80 Effective Date: 07/16 Coding Implications Last Review Date: 06/16 Revision Log

See Important Reminder at the end of this policy for important regulatory and legal information.

Policy/Criteria It is the policy of health plans affiliated with Envolve Pharmacy Solutions® that ecallantide (Kalbitor®) is medically necessary when the following criteria are met:

I. Initial Approval Criteria A. Hereditary (HAE) (must meet all): 1. Age ≥ 12 years; 2. Diagnosis of acute attacks of HAE; 3. Prescribed single dose does not exceed 30 mg. Approval Duration: 2 doses in a 24-hour period

B. Other diagnoses/indications: Refer to ERX.SPMN.16 - Global Biopharm Policy.

Background Description/Mechanism of Action: Kalbitor (ecallantide) is a human plasma inhibitor for injection for subcutaneous use. Ecallantide is a 60-amino-acid protein produced in Pichia pastoris yeast cells by recombinant DNA technology. HAE is a rare genetic disorder caused by mutations to C1- esterase-inhibitor (C1-INH) located on Chromosome 11q and inherited as an autosomal dominant trait. HAE is characterized by low levels of C1-INH activity and low levels of C4. C1-INH functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of plasma kallikrein.

The kallikrein-kinin system is a complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways. One critical aspect of this pathway is the conversion of high molecular weight (HMW) to by the protease plasma kallikrein. In HAE, normal regulation of plasma kallikrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation. Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Kalbitor is a potent (Ki = 25 pM), selective, reversible inhibitor of plasma kallikrein. Kalbitor binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of HMW kininogen to bradykinin. By directly inhibiting plasma kallikrein, KALBITOR reduces the conversion of HMW kininogen to bradykinin and thereby treats symptoms of the disease during acute episodic attacks of HAE.

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FDA Approved Indication: Kalbitor (ecallantide) is a human plasma kallikrein inhibitor/subcutaneous injectable indicated for treatment of acute attacks of (HAE) in patients 12 years of age and older.

Safety Information: Boxed Warning- Anaphylaxis Anaphylaxis has been reported after administration of KALBITOR. Because of the risk of anaphylaxis, KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. Healthcare professionals should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema and patients should be monitored closely. Do not administer KALBITOR to patients with known clinical hypersensitivity to KALBITOR.

Appendices Appendix A: Abbreviation Key HAE: hereditary angioedema

Coding Implications Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services.

HCPCS Description Codes J1290 Injection, ecallantide, 1 mg

Reviews, Revisions, and Approvals Date Approval Date Policy created. 05/16 06/16

References 1. Kalbitor Prescribing Information. Burlington, MA: Dyax Corporation; March 2015.

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Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information.

This Clinical Policy is not intended to dictate to providers how to practice medicine, nor does it constitute a contract or guarantee regarding payment or results. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This policy is the property of Envolve Pharmacy Solutions. Unauthorized copying, use, and distribution of this Policy or any information contained herein is strictly prohibited. By accessing this policy, you agree to be bound by the foregoing terms and conditions, in addition to the Site Use Agreement for Health Plans associated with Envolve Pharmacy Solutions.

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