Evaluating Durable Dysphagia Outcomes in OPMD: Insights From Early BB-301 Clinical Data

Oculopharyngeal muscular dystrophy (OPMD) remains a rare but clinically consequential neuromuscular disease, defined by progressive dysphagia that can lead to aspiration, malnutrition, and significant morbidity over time. Despite the predictable natural history of worsening swallowing dysfunction, treatment options remain limited to supportive care and palliative surgical interventions that do not alter underlying disease biology. As a result, there is a substantial unmet need for disease-modifying therapies capable of stabilizing or improving pharyngeal muscle function in this population.

Against this backdrop, Benitec Biopharma recently announced positive interim Phase 1b/2a data for BB-301, an investigational gene therapy designed to directly address the molecular drivers of OPMD. In this Q&A, Jerel Banks, MD, PhD, Executive Chairman and Chief Executive Officer of Benitec Biopharma, discusses key clinical takeaways from the early data, the rationale behind BB-301’s dual silencing and replacement strategy, and how thoughtful trial design and endpoint selection have helped generate interpretable signals in a historically under-studied disease.

Discuss some of the major takeaways from this phase 1 readout - what stands out from a clinical perspective?

Clinical Trial Results

Jerel Banks, MD, PhD: We are incredibly excited to report that the interim clinical results from our Phase 1b/2a clinical study (NCT06185673) evaluating BB-301 for the treatment of dysphagia in OPMD demonstrate a favorable safety profile for BB-301, as well as durable and robust disease modifying efficacy post-BB-301 administration.

The interim clinical results, capturing patient follow-up ranging from 3 months to 12 months post-BB-301 administration, demonstrated a 100% Response rate for all 6 cohort 1 patients. The first 4 patients in cohort 1 who completed the 12-month statistical follow-up period continue to demonstrate a 100% Response rate, exemplifying durable responses to BB-301.

Additionally, the first patient dosed with BB-301 has completed 24-months of follow-up, and the clinical results further demonstrate the disease-modifying activity of BB-301 with deepening improvements in post-swallow residue clearance and total dysphagic symptom burden.

When compared to the final-pre-treatment timepoint:

• Patient 1 demonstrated durable functional improvement of pharyngeal constrictor-mediated throat closure as determined by VFSS, as the 12-month post-treatment improvement (27% improvement in throat closure at the peak of swallowing) was perfectly maintained at the 24-month post-treatment timepoint (27% improvement in throat closure), indicating durable improvement in pharyngeal muscle function during swallowing
• The throat-emptying ability of Patient 1 continued to significantly improve for liquids and solid food at the 24-month post-treatment timepoint as determined by VFSS (35% reduction in post-swallow residue in the vallecular region of the pharynx at the 12-month post-treatment timepoint, and 60% reduction in post-swallow residue in the vallecular region of the pharynx at the 24-month post-treatment timepoint), exemplifying a deepening of the improvement in swallowing efficiency over time following the administration of BB-301
  • Elevated levels of post-swallow residue in the vallecular region of the pharynx have been shown to correlate with increased risk of aspiration events
• At the 24-month post-treatment timepoint, the total dysphagic symptom burden experienced by Patient 1 continued to significantly decline as determined by SSQ Total Scores (64% reduction in total dysphagic symptom burden as compared to the final pre-treatment assessment at the 12-month post-treatment timepoint, and 78% reduction in total dysphagic symptom burden at the 24-month post-treatment timepoint), exemplifying a deepening of the improvement in total dysphagic symptom burden over time following the administration of BB-301

Study Design

Benitec’s BB-301 clinical development program includes an OPMD Natural History (NH) during which pre-treatment, serial baseline assessments are carried out for each patient over 5 discrete clinical site visits, employing both a patient-reported outcome instrument and comprehensive videofluoroscopic swallowing studies, in order to characterize their total dysphagic symptom burden prior to the administration of BB-301. Subjects diagnosed with OPMD who have previously enrolled into the Benitec NH study and completed at least 6 months of follow-up in the NH study may be eligible to participate in the BB-301 Phase 1b/2a Clinical Trial.

In the BB-301 Phase 1b/2a, Clinical Trial, patients are treated with a one-time administration of BB-301. Post-treatment clinical follow-up visits are comprised of 4 discrete clinical site visits over 1-year and involve comprehensive assessments of dysphagia which are identical to those carried out in the pre-treatment period. The primary objectives of this study are to evaluate the safety of BB-301, to identify the best dose of BB-301 to administer to patients, and to characterize how well BB-301 works to improve the symptoms of dysphagia in patients with OPMD.

Six patients in cohort 1 have been treated with the low dose of BB-301. A Responder Analysis was developed to standardize the evaluation of BB-301 efficacy for each study participant and consists of multiple discrete response categories that collectively assess the dysphagic symptom burden in subjects with OPMD, including patient-reported outcome assessed via the Sydney Swallow Questionnaire (SSQ), videoflouroscopic swallowing study (VFSS) assessments, and functional swallowing capacity (cold water timed drinking test, CWDT).

Disease Overview

OPMD is a serious medical condition. The disorder is a rare, autosomal dominant, muscle-wasting disease characterized by universally progressive dysphagia which can lead to chronic choking, malnutrition, aspiration pneumonia and, in severe cases, death. OPMD is caused by a mutation in the poly(A)-binding protein nuclear 1 (PABPN1) gene.

Without intervention, the dysphagic symptoms universally progress, leading to a significant increase in the dysphagic symptom burden experienced by OPMD patients over time. Evidence of stabilization or improvement in the dysphagic symptom burden of a patient diagnosed with OPMD would represent a clinically meaningful outcome.

Treatment Landscape

The treatment options available for the management of dysphagia in subjects diagnosed with OPMD are limited. No medicinal products have been approved for the treatment of dysphagia in OPMD patients, and no off-label medicinal products have demonstrated significant alterations in the progressive natural history of the dysphagic component of the disease. Current clinical management strategies are comprised of palliative surgical interventions which can provide transient reductions in the dysphagia experienced by some patients, however, in all cases, the pharyngeal constrictor muscles of OPMD patients continue to atrophy, leading to progressive loss of pharyngeal propulsion and clearance of food and liquid into the esophagus.

Provide more commentary on the mechanism and rationale behind BB-301 to treat symptoms of OPMD - why do we believe it can be successful?

BB-301 is a novel investigational gene therapy that combines two distinct biological mechanisms to drive improved muscle function in OPMD. BB-301 delivers an engineered genetic construct that facilitates both the “silencing” of the mutant gene whose mutant protein product drives muscle damage and disease progression and the simultaneous “replacement” of the mutant gene with a functional wildtype gene in a single vector. Silencing of the mutant gene is carried out via DNA-directed RNA Interference (ddRNAi), and traditional gene replacement is used to deliver the new wildtype copy of PABPN1.

BB-301 works to:

1. Block production of the harmful mutant PABPN1 protein
2. Restore normal muscle function by supplying a new, functional version of wildtype PABPN1

In the ongoing BB-301 Phase 1b/2a study, 6 subjects (cohort 1) have received the low-dose of BB-301 and there have been no treatment-related severe adverse events reported for any patient enrolled in cohort 1. All patients in cohort 1 were determined to be Responders to BB-301 treatment, experiencing significant, clinically meaningful improvements in swallowing function and reductions in dysphagic symptom burden.

Proof-of-Concept

In the proof-of-concept studies for BB-301 carried out in the OPMD mouse model, direct intramuscular injection of BB-301 facilitated increases in muscle cross-sectional area, increases in muscle mass, and increases in muscle force generating capacity relative to untreated OPMD mice. In large animal studies, the open surgical procedure employed to achieve the intramuscular injections of BB-301 into the pharyngeal constrictor muscles supported dose-dependent tissue transduction, transgene expression, and target gene knockdown in the injected muscles.

The method of BB-301 administration in the first-in-human study involves open surgical dissection of the pharyngeal region under general anesthesia followed by direct intramuscular injection of BB 301 into the pharyngeal constrictor muscles of patients with OPMD. This allows BB-301 to maximize local benefit while minimizing systemic exposure.

The results of the preclinical studies led to the conclusion that BB-301 injection into the pharyngeal constrictor muscles could, potentially, facilitate biological and clinical improvements in OPMD. Restoration of muscle fiber size and muscle force generating capacity in the weakened and atrophic pharyngeal constrictor muscles of OPMD patients following the use of the optimized route and method of BB-301 administration would be expected to meaningfully enhance the ability of those pharyngeal constrictor muscles to support food bolus propulsion through the pharynx and towards the esophagus, reducing dysphagia in OPMD patients.

What went into the design process of this phase 1/2 trial? Considering there have been relatively few studies testing therapeutics in OPMD

Swallowing represents one of the most frequent physiologic activities, with estimates of spontaneous swallowing approaching up to 400 times per hour. Under normal conditions, a food bolus leaves the oral cavity and is able to traverse the length of the pharynx, en route to the esophagus, via the propulsive activity of the coordinated constriction of the superior, middle, and inferior pharyngeal constrictor muscles. As the food bolus nears the opening of the upper esophagus, the subsequent relaxation of the cricopharyngeal muscle allows the bolus to enter the esophagus and travel to the stomach.

In OPMD, the pharyngeal constrictor muscles are weakened and atrophic and, as a result, are unable to consistently exert the level of force required to support the propulsion of the food bolus that defines the normal swallowing process. The functional sequelae of this aberrant myopathic degradation of the pharyngeal constrictor muscles can lead to post-swallow accumulation of food and liquid residue (inefficient swallowing) and incomplete pharyngeal muscle relaxation post-swallow (ineffective swallowing), with both pathophysiological derangements leading to significant dysphagic symptom burdens for patients diagnosed with OPMD.

BB-301 is designed to facilitate long-term correction of the histological and pathophysiological derangements underlying the natural history of OPMD following a single administration of the medicinal product, as evidenced by preclinical studies.

In rare disease populations there is often a paucity of clinical and natural history data and, typically, there are no indication-specific, clinically-validated endpoints which have been rigorously developed to reproducibly evaluate the efficacy of any medicinal treatments. To date, the Benitec OPMD Natural History Study and the BB-301 Phase 1b/2a Clinical Trial represent the only clinical studies ever conducted which employ serial evaluation of the dysphagic symptom burden of OPMD patients and serial radiographic evaluation of the anatomical and functional elements of swallowing in OPMD patients at a frequency of approximately every 3-months.

As the total dysphagic symptom burden for patients with OPMD has several known underlying contributors, Benitec believes that a multi-component endpoint to evaluate potential treatment effects of BB-301 is most appropriate since it allows for incorporation of multiple assessments that holistically describe disease progression in the pre-treatment setting and the potential clinical benefit in the post-treatment setting following the administration of BB-301. The Responder Analysis was developed to facilitate standardized evaluation of BB-301 efficacy. Each patient enrolled into the BB-301 clinical development program serves as their own control. In this regard, the post-treatment results for each patient are compared to their pre-treatment results to determine the impact of BB-301 on each patient’s total dysphagic symptom burden. Statistical criteria are utilized to determine if response criteria are achieved.

Provide more context on the scales used in the study - how are they representative of the OPMD population and their unmet needs?

Parameters underlying response characterization were derived from literature-based methods previously employed to assess OPMD dysphagic symptom burden, including: SSQ, VFSS, and clinical outcome measures (including the cold water timed drinking test [CWDT]). These methods have been used in the OPMD patient population, as well as other diseases with a dysphagic component, to characterize the severity of dysphagic symptom burden to patients.

What are the next steps following this data? Any preliminary thoughts on what a pivotal study would look like?

We are encouraged by the positive interim clinical results and remain committed to addressing the unmet medical need across this patient population. 2026 is a critical year for Benitec and the BB-301 clinical development program. We look forward to meeting with the FDA in mid-2026 to review the complete clinical results from cohort 1 of the BB-301 Phase 1b/2a Clinical Trial (with 12-months of follow up on all cohort 1 subjects treated) and to discuss pivotal study design.

The putative pivotal study design that will be discussed with the FDA will rely on the same clinical and radiological assessments as employed in the ongoing NH Study and the BB-301 Phase 1b/2a Clinical Trial, incorporating clinical, videofluoroscopic, and subject reported outcome-based assessments. Each study patient would be utilized as their own control via the mandatory completion of a 6-month observational natural history period prior to the administration of BB-301 to facilitate the characterization of their pre-treatment baseline disposition. The BB-301 dose administered to each study patient and the size of the pivotal study population will be determined following statistical analysis of the Phase 1b/2a Clinical Trial results. This registrational study will be designed in accordance with the Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations Draft Guidance for Industry (U.S. Food and Drug Administration, 2025).