First DNA Immunotherapy Approval Masks Thin Single-Arm Surgery-Avoidance Evidence Base

FDA Approves Voceryq for Recurrent Respiratory Papillomatosis

The U.S. Food and Drug Administration (FDA) has granted accelerated approval to Voceryq (doruxapapogene ralaplasmid and lalikinogene sifuplasmid-gxfd) for treating adults with recurrent respiratory papillomatosis (RRP). This marks the first U.S. approval for a plasmid DNA-based immunotherapy, offering a new option for RRP, a rare HPV-caused disease leading to airway growths. The approval was based on clinical trial data demonstrating Voceryq's ability to reduce the frequency of surgical procedures required to remove these growths, addressing the root cause of the disease and potentially lessening the burden of repeated interventions for patients.

• Voceryq is a recombinant plasmid DNA-based immunotherapy designed to stimulate the body's immune system. It delivers two plasmids: one containing genetic instructions for specific HPV proteins (types 6 and 11) and another an immune response-enhancing molecule, IL-12. This mechanism targets and attacks cells infected by the HPV types responsible for RRP.
• The therapy's efficacy was evaluated in an open-label multicenter clinical trial involving 32 adults with RRP. A key outcome showed that 7 out of 26 patients (27%) who had undergone at least three baseline surgeries did not require any further surgical intervention during the first year following Voceryq treatment, demonstrating a reduction in surgical burden.
• Voceryq received Breakthrough and Orphan Drug designations from the FDA, facilitating its accelerated approval. This regulatory pathway allows for earlier access to treatments for serious or life-threatening conditions based on intermediate clinical endpoints, such as the reduction in surgical frequency, which is considered reasonably likely to predict clinical benefit for RRP patients.

Addressing the Relentless Cycle of RRP Surgeries

Currently, no definitive curative treatment for RRP is available; despite the availability of adjunctive treatments, surgery remains the mainstay of treatment. The disease course is unpredictable, ranging from spontaneous remission to aggressive persistent or recurrent disease.

• High surgical burden with cumulative laryngeal morbidity: JoRRP requires substantially more procedures than AoRRP (4-8 vs 1-2 per year), leading to cumulative morbidity, including vocal fold scarring, anterior commissure webbing, glottic or subglottic stenosis, and pulmonary dissemination. In children, 23 patients (46%) sustained laryngeal sequelae, with anterior commissure synechia (17 patients [34%]) followed by glottic stenosis (six patients [12%]), and advanced stages are associated with increased risk of laryngeal sequelae after surgery.

• Limited and controversial adjuvant options with safety concerns: Interferon α and Cidofovir have been shown to lengthen the time between surgical interventions and/or decrease the total number of procedures needed, although the evidence of their efficacy and safety is controversial. It is known to be nephrotoxic when administered intravenously and there remains concern that cidofovir has carcinogenic potential based on animal studies (mammary adenocarcinoma in rats), with no randomized controlled trials and only one case-control study, multiple case series and case reports.

• Rebound, toxicity and access limits of VEGF-targeted therapy: The major concern is the rebound papilloma growth within the cessation of treatment with bevacizumab, with VEGF inhibitors reported to have a range of adverse renal effects, including hypertension, proteinuria, and thrombotic microangiopathy (TMA). The gAdeno-based therapy is the first FDA-approved immunotherapy for RRP; however, with annual treatment costs exceeding USD 300,000, ensuring equitable access remains a critical challenge.

• Risk of distal spread, malignant transformation and mortality: Pulmonary invasion is reported to occur in 3.3% of patients with RRP, and malignant transformation in 0.5% of patients, while extra laryngeal involvement carries the risk of malignant transformation in 3-7% of adults. Children with JORRP and with pulmonary involvement have a higher average number of operations per year than those without pulmonary involvement, with higher mortality rate (OR = 94.909) and increased risk of tracheotomy that could not be decannulated.

• Evidence generation constrained by rarity: The low incidence of RRP does pose significant problems in recruitment of sufficient numbers to show statistical significance, with sufficient clinical follow-up data taking several years. Large multi-centre collaborative clinical trials are therefore required, and prospective multicenter studies are needed to establish optimal treatment protocols and long-term outcomes.

Voceryq's Novel Immunotherapy and Clinical Efficacy in RRP

DNA immunotherapy for recurrent respiratory papillomatosis (RRP): phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107 evaluated INO-3107, DNA immunotherapy designed to elicit T-cells against HPV-6 and HPV-11 (NCT04398433). Thirty-two eligible adults with HPV-6 and/or HPV-11 RRP, requiring ≥2 surgical interventions in the year preceding dosing were enrolled between October 2020 and November 2021 and administered 4 INO-3107 doses by intramuscular injection followed by electroporation. Blood assessments revealed HPV-6 and HPV-11 antigen-specific T-cell induction, RNA sequencing identified an inflammatory response in papillomas, inclusive of cytolytic CD8 + T-cell signatures, and T-cell receptor sequencing revealed emergent T-cell clones in blood and confirmed trafficking to papillomas. Efficacy showed 81% (26/32) of patients experienced surgery reduction following INO-3107 compared with the year prior to treatment, and treatment-related adverse events (AEs) were reported in 13/32 (41%) patients, all low-grade.

PRGN-2012 gene therapy in adults with recurrent respiratory papillomatosis: a pivotal phase 1/2 clinical trial assessed PRGN-2012 in adult patients with RRP treated at the recommended phase 2 dose (NCT04724980). From March 16, 2021, to June 1, 2023, 38 patients were enrolled and received the 12-week treatment course, with adjuvant PRGN-2012 on day 1 following surgical debulking of disease, and on days 15, 43, and 85. Among the 35 patients treated at the recommended phase 2 dose of 5×10 particle units, 18 (51%) of 35 patients had a complete response (95% CI 34-69) with the median duration of complete response yet to be reached, defined as the percentage of patients who did not require an intervention to control RRP in the 12 months after treatment. Adverse events were mild and included grades 1-2 injection site reaction (34 [97%] of 35), fatigue (28 [80%] of 35), chills (25 [71%] of 35), and fever (24 [69%] of 35). Zopapogene imadenovec-drba [Papzimeos; PRGN-2012] is described as FDA-approved for adults.

The Efficacy and Safety of Systemic Treatment for Managing Recurrent Respiratory Papillomatosis: A Systematic Review and Meta-analysis evaluated systemic therapies including systemic bevacizumab and human papillomavirus (HPV)-specific immunotherapies in 35 studies comprising 925 patients. In juvenile-onset RRP, pooled complete remission with systemic bevacizumab was 60% (95% CI 34-87%), and pooled partial response was 46% (95% CI 21-71%). In adult-onset RRP, pooled complete remission with systemic bevacizumab was 44% (95% CI 26-62%), and pooled partial response was 61% (95% CI 43-79%). The most frequently reported bevacizumab adverse events were hypertension (40%), proteinuria (26%), and epistaxis (22%), while HPV-specific immunotherapies (including FDA-approved zopapogene imadenovec-drba [Papzimeos; PRGN-2012] for adults and investigational INO-3107) and PD-1/PD-L1-directed therapies demonstrated encouraging early-phase activity but were too heterogeneous for quantitative pooling.

Reshaping the RRP Treatment Landscape with First-in-Class Approval

Surgical treatment remains the cornerstone of recurrent respiratory papillomatosis (RRP) management; however, aggressive disease often requires frequent procedures with cumulative morbidity. Systemic bevacizumab remains the most mature systemic option with consistent real-world evidence and published dosing guidance. In juvenile-onset RRP, pooled complete remission with systemic bevacizumab was 60% (95% CI 34-87%), and pooled partial response was 46% (95% CI 21-71%). In adult-onset RRP, pooled complete remission with systemic bevacizumab was 44% (95% CI 26-62%), and pooled partial response was 61% (95% CI 43-79%). The most frequently reported bevacizumab adverse events were hypertension (40%), proteinuria (26%), and epistaxis (22%). In a single-center experience of 17 RRP patients, surgical frequency was significantly lower following systemic bevacizumab (2.5 vs. 0.5 surgeries per year; p<0.001), with significant reduction in patients with laryngeal (n=15; 94.1% vs. n=7; 41.2%, p<0.001) and tracheal (n=11; 64.7% vs. n=5; 29.4%, p=0.04) RRP.

HPV-specific immunotherapy has recently transformed adult RRP management with an FDA-approved, short-course treatment option. Zopapogene imadenovec-drba [Papzimeos; PRGN-2012] for adults is the first FDA-approved therapy for RRP, a condition historically managed through repeated surgical debulking. Efficacy and safety data were derived from the pivotal PRGN-2012-201 trial (NCT04724980). In the phase 1/2 PRGN-2012-201 trial (n = 35 at recommended dose), zopapogene imadenovec demonstrated a 51% complete response rate at 12 months (43% at 24 months), an objective response rate of 66%, and no serious treatment-related adverse events. A first-in-human, phase 1 study (NCT04724980) of adjuvant PRGN-2012 treatment in adult patients with severe, aggressive RRP demonstrates overall safety and clinically meaningful benefit with a 50% complete response rate in patients treated at the highest dose. Greater reduction in anatomic Derkay score associated with greater percent reduction in clinically-indicated interventions after PRGN-2012 treatment (r = 0.68, P = 0.0001) and with greater reduction in VHI-10 score (r = 0.81, P < 0.0001).

Investigational HPV-directed and immune checkpoint approaches demonstrate encouraging early-phase activity but were too heterogeneous for quantitative pooling. INO-3107, a DNA immunotherapy designed to elicit T-cells against HPV-6 and HPV-11 and under FDA review, has shown complete response rates from 28% to 50% by year 2. In a 52-week Phase 1/2 study (NCT04398433), 81% (26/32) of patients experienced surgery reduction following INO-3107 compared with the year prior to treatment, and treatment-related adverse events (AEs) were reported in 13/32 (41%) patients, all low-grade. In retrospective extension follow-up, the mean number of surgeries was reduced from 4.1 in the pre-treatment period to 1.7 in the first year post-INO-3107 treatment (Year 1) to 0.9 in the second year (Year 2), and the complete response rate (0 surgeries per year) increased from 28% (9/32) in Year 1 to 50% (14/28) in Year 2. PD-1/PD-L1-directed therapies and dual PD-L1 and TGF-b blockade with bintrafusp alpha remain under investigation, with dual PD-L1/TGF-b inhibition failing to abrogate papilloma growth in most subjects in a phase II trial (NCT03707587 and NCT02859454). Off-label adjuvant therapies such as intralesional cidofovir, intralesional bevacizumab, and HPV vaccination have been used with variable efficacy.

A New Era for RRP: Immunotherapy Targets the Root Cause

The recent FDA accelerated approval of Voceryq for recurrent respiratory papillomatosis (RRP) marks a significant milestone, not just for patients suffering from this debilitating condition, but for the broader field of gene-based immunotherapies. For decades, RRP management has been a relentless cycle of surgical debulking, often requiring numerous procedures throughout a patient's life to maintain airway function and voice quality. This approach, while necessary, is inherently palliative, addressing symptoms rather than the underlying human papillomavirus (HPV) infection. The emotional, physical, and economic toll of these repeated interventions is substantial, and the disease's high recurrence rate has been a persistent challenge.

Voceryq's entry into the market as the first plasmid DNA-based immunotherapy offers a fundamentally different strategy. By inducing an HPV-specific T cell response, it aims to tackle the root cause of RRP, potentially offering durable disease control and significantly reducing the need for frequent surgeries. This represents a crucial shift from symptom management to disease modification, aligning with a growing trend in oncology and rare diseases to develop targeted, curative, or long-term remission-inducing therapies.

However, as with any groundbreaking therapy, several considerations warrant attention:

• While the reduction in surgical frequency is a compelling outcome, the long-term durability of Voceryq's effect and its ability to prevent the rare but serious risk of malignant transformation, particularly in patients with long-standing disease, will be critical to observe.

• The integration of this novel immunotherapy into existing clinical pathways, which have historically relied on surgical and varied adjuvant approaches, will require robust education for clinicians and patients alike.

• Given RRP's recurrent nature and the persistence of HPV infection, ongoing surveillance for disease activity will remain essential, even with this new therapeutic option.

This approval not only provides a much-needed new option for RRP patients but also validates the potential of plasmid DNA technology, opening doors for its application in other HPV-related conditions and chronic viral diseases where current treatments fall short. It underscores a future where precision immunotherapies could redefine the treatment landscape for conditions previously managed through repetitive, invasive procedures.