RARE Daily

Precigen’s Pivotal Study of RRP Gene Therapy Shows Half of Patients Achieve Complete Response

June 4, 2024

Rare Daily Staff

Precigen reported positive phase 1/2 pivotal study results for its investigational PRGN-2012 off-the-shelf gene therapy in patients with recurrent respiratory papillomatosis with 51 percent of patients achieving a complete response, requiring no surgeries after treatment.

Results were presented in a late-breaking oral presentation at the 2024 American Society of Clinical Oncology Annual Meeting.

“We are thrilled with the results of the phase 1/2 pivotal study showing more than half of patients were surgery free–complete response–and 86 percent of patients had a significant reduction in the need for surgeries after PRGN-2012 treatment,” said Helen Sabzevari, president and CEO of Precigen. “Based on the efficacy, safety, and ease of administration, we believe PRGN-2012 is a game-changer for RRP patients and has the potential to be the preferred treatment-of-choice for RRP.”

Recurrent respiratory papillomatosis (RRP) is a rare, difficult-to-treat and sometimes fatal neoplastic disease of the upper and lower respiratory tracts that is caused by infection with human papillomavirus (HPV) 6 or HPV 11. RRP is classified based on age of onset as juvenile or adult. Currently, there is no cure for RRP and the current standard-of-care is repeated endoscopic debulking with ablation or excision of papillomatous lesions. Recurrence of papilloma after surgical removal is very common and repeated procedures are required to debulk and monitor the disease, which exposes patients to anesthetic and surgical risks, and emotional distress. RRP morbidity and mortality results from the effects of papilloma mass on the vocal cords, trachea, and lungs, which may cause voice changes, stridor, airway occlusion, loss of lung volume, and/or post-obstructive pneumonia. Although rare, one to three percent of RRP cases can transform into invasive squamous cell carcinoma.

PRGN-2012 is an investigational off-the-shelf gene therapy designed using Precigen’s AdenoVerse platform to elicit immune responses directed against cells infected with HPV 6 or HPV 11 for the treatment of RRP.

The phase 1/2 clinical study evaluated safety and efficacy of PRGN-2012. The study design included an initial three+three dose escalation cohort to identify the recommended phase two dose (RP2D). Adult RRP patients who had three or more surgeries in the prior 12 months were eligible for the study. The phase 1/2 study enrolled a total of 38 patients. Of these, 3 patients received four administrations of PRGN-2012 at 1x 1011 particle units (PU)/dose and 35 patients received four administrations of PRGN-2012 at RP2D (5 x 1011 PU/dose) over a 12-week treatment period via subcutaneous injection.

Primary endpoints included safety and complete response rate defined as the percentage of patients who require no RRP surgeries in the 12-month period after PRGN-2012 treatment completion. Key secondary endpoints included HPV-specific immune responses, extent of papilloma growth as measured by Derkay scoring, and quality of life measurement as measured by Vocal Handicap Index-10 (VHI-10).

Primary efficacy endpoint analysis demonstrated that 51 percent (18 out of 35) of patients achieved complete response, defined as no need for RRP surgeries in the 12-month period following completion of PRGN-2012 treatment. The complete response rate was 50 percent (6 out of 12) and 52 percent (12 out of 23) in the phase 1 and phase 2 portions of the study, respectively. Complete responses were durable. Median durability of response has not yet been reached with median follow up of 20 months as of the data cutoff date of May 20, 2024. PRGN-2012 treatment significantly reduced the need for surgeries in RRP patients compared to pre-treatment history. PRGN-2012 treatment reduced the need for RRP surgeries in 86 percent (30 out of 35) of patients compared to their pre-treatment history. RRP surgeries were reduced from a median of 4 (range: 3-10) in the 12 months pre-treatment to 0 (range: 0-7) in the 12 months post PRGN-2012 treatment completion.

PRGN-2012 treatment showed significant improvement in anatomical Derkay scores, a tool used for research purposes to quantify RRP severity based on involvement of laryngeal structures, with mean Derkay scores reducing from 9 at baseline to 1 at 24 weeks post-treatment in patients with Complete Response. Quality of life, as evaluated using the validated VHI-10, significantly improved from a mean of 25 at baseline to 7 at 24 weeks post PRGN-2012 treatment in patients with complete response. PRGN-2012 treatment induced HPV 6/11-specific T cell responses in RRP patients with a significantly greater expansion of peripheral HPV-specific T cells observed in responders compared with non-responders.

PRGN-2012 treatment was well-tolerated with no dose-limiting toxicities and no treatment-related adverse events (TRAEs) greater than Grade 2. All patients received four administrations of PRGN-2012 at the intended dose levels. TRAEs were mostly mild with no treatment-related serious adverse events reported. The most common TRAE was injection site reaction. Other common TRAEs occurring in more than one subject were fatigue, chills, and fever. There was no meaningful anti-drug antibody response with repeat administrations of PRGN-2012.

PRGN-2012 has been granted Orphan Drug and Breakthrough Therapy designations in patients with RRP by the U.S. Food and Drug Administration and Orphan Drug designation by the European Commission.

Precigen will share these results with the FDA as part of a rolling Biologics License Application submission under an accelerated approval pathway. Sabzevari says the company has ramped up its commercial readiness efforts in anticipation of a potential launch in 2025.

Photo: Helen Sabzevari, president and CEO of Precigen

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