CurrentCignaPolicy IP0096

Hereditary Angioedema - Orladeyo

This Cigna Coverage Policy governs prior authorization and coverage criteria for Orladeyo (berotralstat capsules and oral pellets) when used for prophylaxis of hereditary angioedema (HAE) due to C1 inhibitor deficiency, and applies to members whose plans follow Cigna's Coverage Policies.

Policy Summary

PayerCigna

PolicyHereditary Angioedema - Orladeyo

Policy CodePolicy IP0096

Change TypeMultiple operational and clinical revisions

Effective Date

Next Review Date

Key ActionObtain prior authorization and document baseline low functional C1‑INH and low serum C4; approve for 1 year if criteria are met.

SourceLink

POLICY UPDATE CHANGES

Initial therapy age requirement changed from ≥ 12 years to ≥ 2 years of age.

Orladeyo oral pellets (new formulation) were added to the policy with the same requirements applied as the tablets.

Indication name clarified to 'Hereditary Angioedema (HAE) Due to C1 Inhibitor (C1-INH) Deficiency - Prophylaxis'.

Requirement for confirmed pathogenic variant in SERPING1, F12, ANGPT1, PLG, or KNG1 genes was removed.

Requirement for low C1-INH antigenic levels (less than 50% of normal) at baseline was removed.

Added requirement that medication be prescribed by or in consultation with a physician who specializes in HAE or related disorders.

≥2Minimum age for initial Orladeyo approval

1 yearApproval duration

type I/IIEligible HAE types

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Coverage Criteria — Orladeyo (berotralstat)

FDA-Approved Indication — Hereditary Angioedema (HAE) Due to C1-INH Deficiency — Prophylaxis

Approve for 1 year if the patient meets ONE of the following (A or B):

A or B: A. Initial therapy OR B. Patient currently receiving Orladeyo

A. Initial therapy: Patient must meet all of i, ii, and iii

A.i Age: Patient is >= 2 years of age>= 2 years

see revision details

A.ii Diagnostic confirmation: HAE type I or II confirmed by: a) functional C1-INH protein <50% of normal at baseline and b) lower than normal serum C4 at baselinefunctional C1-INH <50%; low C4 per lab ref

HAE-nC1INH/type III does NOT satisfy this requirement; documentation required

A.iii Prescriber: Medication prescribed by or in consultation with an allergist/immunologist or physician who specializes in HAE or related disorders

documentation required

B. Currently receiving Orladeyo: Patient has diagnosis of HAE type I or II; prescriber documents favorable clinical response since initiating Orladeyo compared with baseline; medication prescribed by or in consultation with an HAE specialist

If patient is receiving Orladeyo but prior approval was not previously obtained, review under Initial Therapy criteria

Orladeyo (berotralstat) is not medically necessary when used for any indication other than prophylaxis of hereditary angioedema (HAE) due to C1‑INH deficiency. Requests for coverage of Orladeyo for other diagnoses or clinical scenarios will be denied as not medically necessary.

Long‑term concomitant use of Orladeyo with other HAE prophylactic therapies (for example, Cinryze, Haegarda, or Takhzyro) for ongoing prophylaxis is not recommended and considered not medically necessary, because Orladeyo has not been studied in combination with other prophylactic agents for long‑term use. Short‑term or procedural prophylaxis considerations are separate and should follow guidance for the specific clinical situation.

Orladeyo should not be used in combination with other HAE prophylactic therapies for long‑term prophylactic treatment; such combination therapy is considered not medically necessary. The policy notes that Orladeyo has not been studied in combination with other prophylactic agents and that examples of other prophylactic therapies include intravenous or subcutaneous C1‑esterase inhibitor products and lanadelumab.

Use of Orladeyo for indications other than HAE due to C1‑INH deficiency (including HAE with normal C1‑INH/type III) is considered not medically necessary and is excluded from coverage under this policy.

Coding and Laboratory Thresholds

Covered CPT Codesmixed

No codes listed

Functional C1-INH level — baseline threshold reference

Functional C1-INH thresholdFunctional C1-INH protein < 50% of normal at baseline as defined by laboratory reference values (documentation required)

PurposeDiagnostic confirmation of HAE type I or II for initial Orladeyo therapy

When requiredRequired for initial therapy and for documentation of diagnosis when patient is currently receiving Orladeyo without prior approval

Serum C4 level — laboratory expectation (lower than normal)

Serum C4 expectationSerum C4 level lower than laboratory normal at baseline (per laboratory reference values)

Role in diagnosis

Provider Actions — Authorization, Documentation, and Denials

Prior Authorization

Prior Authorization Required

Prior authorization is required for coverage of Orladeyo. Approval requires prescription by or consultation with a physician who specializes in the condition being treated. Approvals are provided for the duration noted in the policy (typically 1 year for approved indications). If a patient is currently receiving Orladeyo and has previously met initial therapy criteria under the Coverage Review Department, only continuation therapy criteria are required; if past criteria were not met under the Coverage Review Department, the patient must meet initial therapy criteria.

Prior authorization required for Orladeyo
Approval duration: typically 1 year for approved indications
Prescriber requirement: prescribed by or in consultation with an allergist/immunologist or physician specializing in HAE or related disorders

Documentation Required

Documentation is required where noted in the criteria (marked as [documentation required]). Documentation may include, but is not limited to, chart notes, laboratory records, and prescription claims records. All documentation must include patient-specific identifying information and should substantiate diagnostic criteria, baseline laboratory values, and clinical response as applicable.

Definitions — HAE Phenotypes

HAE type I/II — diagnostic characterization

Diagnostic featuresHAE type I/II characterized by low functional C1‑INH levels (<50% of normal) and low serum C4 at baseline

Evidence basePivotal trials (e.g., APeX2) enrolled patients with type I or II HAE confirmed by C1‑INH functional level and C4 levels

Guideline alignmentUS HAE Association guidelines recommend measuring serum C4 and C1‑INH antigenic and functional levels; low C4 plus low C1‑INH supports HAE I/II diagnosis

HAE‑nC1INH (type III) — description and policy exclusion rationale

DefinitionHAE‑nC1INH (also called HAE type III) refers to hereditary angioedema with normal C1‑INH levels; it is challenging to diagnose biochemically

Policy stance

Background — Drug and Indication

Orladeyo (berotralstat) is an oral plasma kallikrein inhibitor indicated for prophylaxis to prevent hereditary angioedema (HAE) attacks in patients with HAE due to C1‑INH deficiency. It is approved for prophylactic use and is not indicated for treatment of acute HAE attacks.

The policy was updated to reflect the product name Orladeyo and expanded to include both capsule and oral pellet formulations; it also clarifies the indication as HAE due to C1‑INH deficiency (type I or II) and notes that combination long‑term prophylactic use with other HAE agents has not been evaluated.