Zopapogene Imadenovec-drba (Papzimeos)

Number: 1090

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses zopapogene imadenovec-drba (Papzimeos) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of zopapogene imadenovec-drba (Papzimeos) is required of all Aetna participating providers and members in applicable plan designs. For precertification of zopapogene imadenovec-drba (Papzimeos), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with an otolaryngologist or a specialist in the treatment of recurrent respiratory papillomatosis.

2. Criteria for Initial Approval

   Aetna considers a one-time treatment course of 12 weeks (4 doses) of zopapogene imadenovec-drba (Papzimeos) medically necessary for the treatment of recurrent respiratory papillomatosis (RRP) in adult members when all of the following criteria are met:

   1. Member has a clinical diagnosis of recurrent respiratory papillomatosis defined by all of the following:

      1. Presence of laryngotracheal papillomas; and
      2. Histological diagnosis of papilloma confirmed by pathology report; and
      3.  Member has documented human papillomavirus (HPV) serotype 6 or 11; and
   2. Member has had 3 or more debulking procedures to remove laryngotracheal papillomas in the 12 months prior to treatment with Papzimeos; and
   3. Prescriber attests to both of the following criteria:
      
      
      1. Surgical debulking of visible papilloma will be performed prior to initial administration to establish minimal residual disease; and
      2. If present, visible papillomas will be removed to maintain minimal residual disease prior to the third and fourth administration of Papzimeos; and
   4. Member has not received more than 4 doses (one-treatment course) of Papzimeos; and
   5. Papzimeos will not be used in combination with other medications used for the treatment of RRP (e.g., bevacizumab, cidofovir); and
   6. Member has a negative serology test for hepatitis B (HBV) and hepatitis C (HCV).

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Related Policies 

   1. CPB 0685 - Bevacizumab for Non-Ocular Indications

Dosage and Administration

Papzimeos is a sterile, frozen suspension supplied in single-dose vials containing 5×10¹¹ particle units (PU) in 1 mL, intended for subcutaneous injection only. Each vial is aseptically sealed and packaged with a product insert inside a carton, which is shipped and stored at temperatures ≤ -60°C (≤ -76°F) using dry ice. Upon receipt, the product must remain frozen until use, at which point it must be rapidly thawed and administered immediately.

The recommended dosing regimen for Papzimeos is 5×10¹¹ PU administered subcutaneously in the upper arm or thigh 4 times over a 12-week period. Prior to the first dose, surgical debulking of visible papillomas is required to establish minimal residual disease. To maintain this minimal disease state during treatment, any visible papillomas should be removed again prior to the third and fourth injections.

Source: Precigen, 2025

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J3404	Injection, zopapogene imadenovec-drba suspension, per therapeutic dose
ICD-10 codes covered if selection criteria are met:
B97.7	Papillomavirus as the cause of diseases classified elsewhere
D14.1	Benign neoplasm of larynx [Recurrent respiratory papillomatosis]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Papzimeos is indicated for the treatment of adults with recurrent respiratory papillomatosis.

Zopapogene imadenovec-drba, marketed as Papzimeos (Precigen, Inc.), is an innovative immunotherapy utilizing a non-replicating adenoviral vector to express a fusion antigen derived from specific regions of human papillomavirus (HPV) proteins associated with HPV 6 and HPV 11. This therapy is designed to elicit an immune response against HPV proteins in patients with recurrent respiratory papillomatosis (RRP).

Papzimeos, administered as a subcutaneous injection, includes labeled warnings and precautions for injection-site reactions and thrombotic events, which may result from the induction of prothrombotic antibodies associated with adenoviral vector-based therapies. The most commonly reported adverse reactions, occurring in 5% or more of patients, are injection site reactions, fatigue, chills, pyrexia, myalgia, and nausea.

There are no human or animal data evaluating the reproductive or developmental toxicity of Papzimeos. In a clinical study (PRGN-2012-201), one patient became pregnant six months after completing treatment and delivered at 40 weeks without reported birth complications or neonatal concerns. The general U.S. population has an estimated background risk of 2-4% for major birth defects and 15-20% for miscarriage in clinically recognized pregnancies. No data are available regarding the presence of Papzimeos in human milk, its potential effects on a breastfed infant, or its impact on milk production. Decisions regarding breastfeeding should consider the clinical necessity of Papzimeos for the mother and any potential risks to the infant. Additionally, Papzimeos has not been evaluated for safety or efficacy in pediatric populations.

Recurrent Respiratory Papillomatosis

Recurrent respiratory papillomatosis (RRP) is a rare and chronic disorder caused by persistent infection with human papillomavirus (HPV) types 6 or 11, leading to the development of wart-like growths (papillomas) in the respiratory tract, particularly the larynx and the vocal cords (laryngeal papillomatosis). This condition results in significant morbidity, including debilitating voice changes and airway obstruction, necessitating numerous surgical debulking procedures throughout a patient's life. RRP can affect both adults and children, with transmission occurring through sexual contact or from mother to child during childbirth. The RRP Foundation estimates approximately 20,000 active cases in the U.S., with juvenile-onset RRP occurring in about two cases per 100,000 children and adult-onset RRP in two to three cases per 100,000 adults, although the exact incidence remains unclear. Although papillomas are considered benign, in rare cases, it may exhibit aggressive growth, spread to the lungs, and undergo malignant transformation.

RRP involving the trachea or bronchi is primarily managed through local debulking therapies, as airway obstruction typically results from bulky papillomatous growth rather than discrete stenosis. Debulking is achieved via flexible or rigid bronchoscopy using mechanical tools such as forceps or microdebriders, or thermal ablative methods like laser or electrocautery. Adjunctive treatments, including intralesional cidofovir and photodynamic therapy, have shown limited success in case reports. Approximately 20% of patients receive systemic therapies—such as interferon gamma, cidofovir, indole-3-carbinol, celecoxib, bevacizumab, and HPV vaccination—though use is variable and clinician-dependent. In refractory or recurrent cases, surgical intervention or tracheostomy may be necessary. Zopapogene imadenovec (PRGN-2012), a non-replicating adenoviral vector-based immunotherapy, has emerged as a novel therapy for RRP (Shepherd and Radchenko, 2025).

PRGN-2012, a gorilla adenovirus-based immunotherapy, is designed to stimulate HPV 6/11-specific T cell responses. In this first-in-human phase 1 trial (NCT04724980), PRGN-2012 demonstrated a favorable safety profile and a 50% complete response rate at the highest dose level. Responders exhibited enhanced peripheral HPV-specific T cell expansion and tumor microenvironment features such as lower baseline HPV gene expression, increased interferon signaling, and elevated CXCL9/CXCL10 chemokine levels, along with greater T cell infiltration. In contrast, nonresponders showed higher HPV and CXCL8 expression, increased neutrophilic infiltration, and reduced T cell presence within papillomas. These results suggest that papilloma HPV gene expression may regulate interferon signaling and chemokine expression profiles within the tumor microenvironment that cooperate to govern clinical response to therapeutic HPV vaccination in patients with respiratory papillomatosis (Norberg et al., 2023).

Norberg SM et al. (2025) conducted a single-center, single-arm, phase 1/2 clinical trial evaluating the safety and efficacy of PRGN-2012, an investigational gene therapy, in adults with recurrent respiratory papillomatosis (RRP). The study enrolled 38 patients (aged 18 years or older) between March 2021 and June 2023, with 35 receiving the recommended phase 2 dose of 5×10¹¹ particle units (PU). The primary endpoint was complete response rate, defined as the proportion of patients not requiring surgical intervention for RRP within 12 months post-treatment. Among those treated at the target dose, 51% (18/35; 95% CI 34–69) achieved a complete response, with the median duration of response not yet reached. Safety outcomes were favorable, with only mild grade 1–2 adverse events reported, including injection site reactions (97%), fatigue (80%), chills (71%), and fever (69%). The authors concluded that PRGN-2012 demonstrated promising clinical activity and a favorable safety profile, supporting its potential as the first FDA-approved systemic therapy for RRP.

In August 2025, the FDA granted Priority Review approval for Precigen's Papzimeos, a subcutaneous immunotherapy for adult patients with RRP. Approval was based on data from a single-arm, open-label trial (PRGN-2012-201; NCT04724980) that successfully met its primary safety and pre-specified primary efficacy endpoints.

The PRGN-2012-201 study evaluated the efficacy of Papzimeos in 38 adults with RRP who had undergone 3 or more debulking procedures in the prior 12 months. All patients received subcutaneous injections on Days 1, 15, 43, and 85 following a standard-of-care surgical debulking. Of the 38 patients, 3 patients were treated with Papzimeos at a dose of 1×10¹¹ particle units (PU) per injection. Thirty-five patients were treated at a dose of 5×10¹¹ PU per injection and were included in the efficacy evaluation. The primary endpoint was complete response, defined as no need for surgical intervention within 12 months post-treatment. At the 5×10¹¹ PU dose, 18 of 35 patients (51%; 95% CI: 34–69%) achieved a complete response at 12 months, with 15 maintaining response at 24 months (43%; 95% CI: 26–61%). None of the 3 patients treated with the lower dose of 1×10¹¹ PU achieved a complete response. Additionally, Papzimeos demonstrated a favorable safety profile, with no dose-limiting toxicities or Grade greater than 2 adverse events.

Papzimeos also received Orphan Drug and Breakthrough Therapy designations.

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References