Clinical deep dive 

RRP is a rare condition which manifests clinically as persistent wart-like growths (papillomas) within the aerodigestive tract, primarily in the larynx, trachea and lungs. The disorder has a variable course, and it is difficult to predict the timing and severity of disease recurrence. It is typically classified as juvenile-onset or adult-onset disease; cases diagnosed before the age of 12 have been considered juvenile-onset RRP (JO-RRP), while cases onsetting after 12 years of age have been classified as adult-onset RRP (AO-RRP). The most common symptom of RRP is hoarseness. Additionally, some patients may present with dysphonia, aphonia, dysphagia, dyspnea, sensation of a foreign body in the throat, chronic cough and choking episodes. Voice problems may vary from patient to patient depending on factors such as the size and location of the papillomas. Patients may also develop stridor if there is airway obstruction. Infants may present with a weak cry, choking episodes and failure to thrive. Life-threatening breathing difficulties may develop if the condition is left untreated. When RRP affects the lungs, recurrent pneumonia, chronic lung disease and pulmonary failure may develop. Studies have demonstrated increased levels of social anxiety and feelings of debilitation with many patients avoiding social activities due to voice impairment. Rarely, patients may experience malignant transformation of the papillomas in less than 1% of RRP cases.  

RRP is caused by HPV. Of the more than 150 subtypes of HPV, infection with HPV 6 and HPV 11 results in more than 90% of RRP cases. It is estimated that approximately 75% to 80% of men and women will be impacted by HPV during their lives if they are not vaccinated. The most likely cause of HPV transmission in children is passage from an affected mother to the baby during childbirth while the child passes through the birth canal; however, other factors (such as immunologic or genetic) are also required for the development of RRP in patients with HPV. The mode of transmission in adults is less apparent with some cases onsetting due to latent infection during infancy which later triggers in adulthood. Evidence also suggests that AO-RRP can be obtained through sexual transmission. 

A systematic review identified the incidence and prevalence of JO-RRP as 0.2 to 2.1 per 100,000 and 0.8 to 4.3 per 100,000, respectively, while the incidence and prevalence of AO-RRP were 0.2 to 3.9 per 100,000 and 0.4 to 8.4 per 100,000, respectively. Moreover, the manufacturer estimates that there are approximately 27,000 adult patients in the U.S. with RRP. A recent study conducted in the U.S. found declining JO-RRP incidence, which was attributed likely to HPV vaccination. 

Currently, there is no cure for RRP nor are there any FDA-approved treatment options for this condition. As such, the current mainstay of RRP treatment consists of surgical excision of the papillomas to ensure a safe and patent airway and improve voice quality while preserving anatomical structures. The recurrence of papillomas is unpredictable in clinical practice. In a minority of cases, RRP can lead to spontaneous remission; however, most cases require multiple surgical treatments and adjuvant medical therapy. Surgical procedures include cold excision, microdebridement, various pulsed dye lasers or carbon dioxide lasers. Medications such as acyclovir, ribavirin, cidofovir and interferon are utilized to delay the regrowth of papillomas and increase the time between surgeries. Additionally, the vascular endothelial growth factor (VEGF) inhibitor bevacizumab has shown promise as a treatment for RRP. The Gardasil 9 HPV vaccine may have a potential benefit for RRP treatment and primary prevention.  

Drug and clinical trial overview 

The safety and clinical activity of zopapogene imadenovec were evaluated in a single-center, single-arm Phase 1/2 clinical trial. Eligible patients were 18 years of age or older with a diagnosis of RPP, which was defined as a histological diagnosis of papillomas, presence of laryngotracheal papillomas and a history of three or more clinically indicated interventions in the 12 months before treatment. Additionally, patients had to have a Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. The primary outcome was complete response rate, which was defined as the percentage of patients with no clinically indicated interventions during the 12 months after treatment. Clinically indicated interventions were characterized by surgical resection of disease under general anesthesia or laser ablation under local anesthesia. Thirty-five patients were treated at the recommended phase 2 dose (5x10¹¹ particle units per injection) from the phase 1 and 2 studies. Prior to the first administration of zopapogene imadenovec, patients underwent a standard of care surgery. Patients received four subcutaneous injections of zopapogene imadenovec (days 1, 15, 43 and 85) with up to two optional debulking surgeries if papilloma regrowth occurred during the 12-week treatment period. The complete response rate in this patient population was 51% (18/35); the median duration of response had not been reached as of the data cutoff date. These responses were durable, as demonstrated by 83% (15/18) of patients requiring no clinically indicated interventions beyond the 12 months after treatment. Five of 35 patients (14%) achieved a partial response, which was defined as a 50% or greater reduction in clinically indicated interventions after treatment as compared to before treatment. As such, the objective response rate was 66% (23/35). In the 12 months following treatment, 30 out of 35 patients (86%) experienced a decrease in clinically indicated interventions compared to the 12 months prior to treatment. Complete responders required a median of 4 clinical interventions within the 12-month pretreatment period while non-complete responders required a median of 3. In the 12-months after treatment, complete responders required a median of 0 clinical interventions while the non-complete responders required a median of 2 (p<0.0001). Six months after treatment, patients showed improvements in both the Derkay score, which measures papillomatosis disease burden and the Vocal Handicap Index-10 (VHI-10), which reflects how patients perceive their vocal handicap. Among the complete responders, a median percent reduction of 90% and 95% were seen in the Derkay and VHI-10 scores, respectively. Treatment with zopapogene imadenovec was well tolerated with the most common adverse events being injection-site reaction (97%), fatigue (80%), chills (71%), fever (69%) and myalgia (26%). These adverse events occurred more commonly after the first administration of the product and generally lasted one to three days. No treatment related serious adverse events occurred. Additionally, there were no adverse events leading to discontinuation, and there were no grade 3 or greater treatment related adverse events.