Clinical deep dive 

RRP is a rare condition which manifests clinically as persistent wart-like growths (papillomas) that can occur anywhere within the respiratory tract, most commonly in the larynx and vocal cords and, rarely, in the 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). Juvenile cases tend to be more aggressive and recurrent. 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 approximately 14,000 people in the U.S. are affected by RRP. A recent study conducted in the U.S. found declining JO-RRP incidence, which was attributed likely to HPV vaccination. 

Papzimeos is currently the only FDA-approved treatment for RRP in adults. According to the RRPF position statement, HPV-specific immunotherapy is recommended as first-line medical treatment for patients seeking to avoid the risks associated with repeated procedural management. The RRPF position statement also recommends systemic bevacizumab as second-line medical treatment for patients without a complete response to immunotherapy and prefer to continue medical management. In addition, the position statement recommends administration of Gardasil 9 in all adult RRP patients if not previously vaccinated. 

Before the availability of Papzimeos, RRP management mainly consisted 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. Medical therapies, including antivirals (acyclovir, ribavirin and cidofovir), bevacizumab and the Gardasil 9 HPV vaccine, have also been used off-label as adjuvant therapy to delay the regrowth of papillomas and increase the time between surgeries.  

Drug and clinical trial overview 

The efficacy and safety of INO-3107 were evaluated in a 52-week Phase 1/2, single-arm, open-label trial (RRP-001). Eligible patients were 18 years of age and older with histologically documented HPV-6 and/or HPV-11 positive-RRP. Additionally, patients were required to have a history of two or more surgical interventions for RRP in the year prior to treatment. All patients were required to undergo a surgical intervention within 14 days of the first dose. INO-3107 was administered IM at a dose of 6.25 mg on Day 0 and Weeks 3, 6 and 9. Each of the four IM injections was followed immediately by EP using the CELLECTRA device, which is a proprietary device designed to enable local transfection of DNA plasmids into the cells. The primary endpoint was safety and tolerability, reported by treatment-emergent adverse events (TEAEs) and serious adverse events (SAE). Efficacy, a secondary endpoint, was assessed by comparing the number of RRP surgical interventions in the year following Day 0 compared with the prior year. A total of 32 patients were enrolled in the trial, of which 26 had a clinical response (81.3%), which was defined as a reduction of at least one surgical procedure in the year following Day 0 (overall clinical response; OCR). Complete response (CR) and partial response (PR) were defined as no surgical interventions and a 50-99% reduction in the number of surgical interventions, respectively, in the year following Day 0; 9 patients (28.1%) had a CR, and 14 additional patients (43.8%) had a PR. INO-3107 was well tolerated. Twenty patients (62.5%) reported TEAEs, the majority of which were treatment-related (35 of 58 events). All related TEAEs were Grade 1 or 2 in severity with injection site pain being the most common, occurring in 10 patients. SAEs were reported in 3 patients (9.4%), but none were considered treatment-related.  

In a retrospective, observational extension study (RRP-002) that followed patients enrolled in the aforementioned RRP-001 trial, 28 patients were enrolled, and the long-term efficacy and tolerability of INO-3107 were evaluated for up to an additional three years. The median follow-up time for RRP-002 was 1.8 years (range: 1.2-2.4 years) with a total median follow-up time of 2.8 years across RRP-001 and RRP-002 (range 1.0-3.5 years). In the 52-week pre-treatment period the mean number of annual surgeries was 4.1, which was reduced to 1.7 and 0.9 at Year 1 and Year 2, respectively. Overall, this finding demonstrates a 78% reduction in mean annual surgeries in Year 2 compared to the 52-week pre-treatment period. Complete Year 3 data was not available for all patients, but available data indicate that the mean decrease in the number of annual surgeries persists into Year 3. The percentage of patients who achieved a CR increased to 50% (14/28) in Year 2. No treatment-related SAEs were reported, and no long-term safety concerns were observed.