FDA Lends a Single Arm: Papzimeos Approval Highlights FDA’s Willingness to Rely on Single-Arm Trials for Rare Diseases

FDA’s recent approval of Papzimeos (zopapogene imadenovec-drba) highlights FDA’s use of regulatory flexibility in rare, serious diseases with unmet medical need. Approved on August 14, 2025, Papzimeos is the first treatment in the U.S. for recurrent respiratory papillomatosis (RRP), a rare disease characterized by recurrent HPV-induced papillomas in the airway that often require repeated surgeries. Papzimeos, a non-replicating adenoviral vector-based immunotherapy, is designed to stimulate a patient’s immune system to tackle the virus-infected cells driving disease. According to FDA’s announcement of the approval and the product’s labeling, approval of Papzimeos was based on a single-arm, open-label Phase 1/2 dose escalation plus dose expansion study that evaluated the safety and efficacy of Papzimeos in adult RRP patients – specifically patients who had three or more surgeries in the prior 12 months.

In FDA’s announcement, the current Center for Biologics Review Director, Dr. Vinay Prasad, stated

Randomized trials are not always needed to approve medical products and this approval is proof of that philosophy. The FDA will always demand the correct clinical study for the specific medical product and disease. Our requirements for products given to tens of millions of healthy people will be different than products given to at most hundreds or thousands of patients with unique diseases.

This is an important endorsement by new FDA leadership.

FDA’s regulatory framework has long contemplated baseline-controlled and other historically-controlled trials as being capable of establishing drug effectiveness. The December 2019 Draft Guidance: Substantial Evidence of Effectiveness for or Human Drug and Biological Products explains that the substantial evidence of effectiveness standard requires expert judgment, including in accepting study designs that “produce less certainty” than randomized, controlled studies.  The May 2001 Guidance for Industry: E10 Choice of Control Group and Related Issues in Clinical Trials explicitly recognizes the baseline-controlled study as a type of historical control group that is appropriate in certain circumstances. Specifically in the context of rare diseases, FDA has recognized that “single-arm trials may be an important option in rare diseases with well-understood pathophysiology and a well-defined disease course,” (FDA’s May 2014 Draft Guidance: Expedited Programs for Serious Conditions – Drugs and Biologics).  And, at its core, historical controls are recognized in regulation as capable of being “adequate and well-controlled studies” that can support FDA’s effectiveness conclusions (21 C.F.R. § 314.126).

However, acceptance of non-traditional study designs by regulators requires exercise of judgment, and Agency leadership play an important role in doing so.  However, as Dr. Prasad notes, there are certain circumstances where baseline-controlled studies are most appropriate.

The Papzimeos Approval Helps Us Understand Circumstances Where Baseline-Controlled Studies Are Appropriate

The primary efficacy endpoint in the Phase 1/2 study of Papzimeos was Complete Response, defined as the percentage of patients requiring no RRP surgeries in the 12 months following treatment. Key secondary endpoints included HPV-specific immune responses, extent of papilloma growth as measured by Derkay scoring, and quality of life as measured by the Vocal Handicap Index-10 (VHI-10).

Precigen, the drug’s sponsor, announced in August 2023 that it had gained agreement with FDA that the Phase 1/2 study could serve as a single pivotal trial to support accelerated approval utilizing HPV-specific immune response as a surrogate endpoint. However, when FDA issued its approval decision this month, it went further, granting traditional, or full, approval instead. While the approval package is not yet publicly available to provide insight into FDA’s reasoning for supporting a single-arm pivotal trial design, these authors believe the choice of a single-arm study design was particularly well-suited for RRP.

1. As noted by FDA’s Dr. Prasad, RRP is rare, affecting approximately 27,000 adults in the United States. FDA has a history of applying flexibility for rare diseases, as well as for serious conditions with unmet medical needs.  RRP was all these things, with no FDA-approved therapy for this disease, which is characterized by recurrent, rapidly growing papillomas in the upper and lower respiratory tract that cause severe and potentially fatal airway obstruction, chronic lung disease, and recurrent pneumonia, thus requiring frequent surgeries.
2. Because recurrence of papillomas after surgery is nearly universal, a single-arm study allows for meaningful comparison against the known natural history of the disease because lack of recurrence (defined as being surgery-free for the study duration) can reliably be attributed to treatment effect. This is analogous to solid tumor response in cancer treatment, where spontaneous tumor regression is exceedingly rare and, as a result, single-arm studies have been a mainstay.
3. To enroll a population with severe enough disease to detect a treatment effect in a 12-month duration study (i.e., to adequately enrich the study), the study recruited RRP patients with three or more surgeries in the prior 12 months. This means that patients are more likely to have recurrence and require additional surgeries if left untreated.  It would not be ethical to randomize patients to forego off-label drug therapy often used in conjunction with surgery (e.g., Avastin, Cidofovir) in lieu of placebo for 12 months.  It would likely be infeasible to recruit such a study, as the more severe patients targeted for enrichment are likely to pursue off-label treatment if faced with the possibility of being randomized to placebo.
4. The treatment hypothesis for the primary endpoint was (1) objective (surgery) and (2) of a large magnitude (Complete Response), two key features that help reduce or overcome bias that can be associated with open-label trials. Knowledge of treatment assignment is unlikely to influence their perceptions, behaviors, and reporting of outcomes associated with surgical intervention as an outcome.
5. The combination of a well understood disease pathophysiology, such as HPV-induced papillomas in RRP, together with a therapy that has a mechanism of action on the causal pathway of the disease, such as Papzimeos which generates HPV 6- and HPV-11 specific T cell responses (see Section 12 of the product’s labeling), provides confidence that a deviation from the expected natural history is more credibly attributed to the drug despite the lack of concurrent control.

The Papzimeos Approval Does Not Stand Alone

This approval is one of a number of recent examples over the past year that demonstrate the ability of a single-arm study to establish effectiveness in a rare disease setting. From August 2024 to date, of the 22 novel, non-oncology rare disease drug approvals by FDA, nearly 20% (n=4) were on the basis of a single-arm trial; beyond Papzimeos, they are:

• November 13, 2024 approval of Kebilidi (eladocagene exuparvovec-tneq) for aromatic L-amino acid decarboxylase (AADC) deficiency;
• December 18, 2024 approval of Ryoncil (remestemcel-L-rknd) for steroid-refractory acute graft versus-host disease (SR-aGvHD); and
• February 11, 2025 approval of Gomekli (miradmetinib) for neurofibromatosis type 1 (NF1).

Each of these cases underscores the FDA’s recognition, across both CDER and CBER, that evidentiary requirements for meeting substantial evidence of effectiveness must be tailored to the context of the product and the patient population. For RRP patients, Papzimeos represents a long-awaited therapeutic option, and for the broader rare disease community, it serves as another illustration of how regulatory flexibility can accelerate access to transformative therapies while still upholding rigorous scientific standards.