Benitec Biopharma’s Oculopharyngeal Muscular Dystrophy Gene Therapy Produces Clinical Improvements in Swallowing in Phase 1b/2a Trial
Benitec reported that the first patient showed a 35% reduction, constituting clinically meaningful improvement, in total score on the Sydney Swallow Questionnaire.
Benitec Biopharma’s BB-301, an investigational adeno-associated virus (AAV) vector-based silence and replace gene therapy for the treatment of oculopharyngeal muscular dystrophy (OPMD)-related dysphagia, has demonstrated the ability to clinically improve swallowing in the first 2 patients treated in a phase 1b/2a clinical trial (NCT06185673).1 The results were presented at the 29th Annual Congress of the World Muscle Society, held in Prague, Czech Republic, 8 to 12 of October.
Benitec reported that the first patient (Patient 1), who had 270 days of posttreatment follow-up, showed a 35% reduction, constituting clinically meaningful improvement, in total score on the Sydney Swallow Questionnaire (SSQ), with a 42% improvement recorded for thin liquid, a 16% improvement for solid food, and a 22% improvement for thick liquids. Furthermore, Patient 1 also demonstrated improvements on videofluoroscopic swallowing study assessments of total pharyngeal residue (VFSS TPR). Specifically, the patient showed a 33% improvement for thin liquid, an 18% improvement for solid food, and a 30% improvement for thick liquids. The comparisons were measured with reference to the patient’s average values for 5 visits during the Benitec-sponsored OPMD Natural History (NH) Study, which the patient crossed over from. The company noted that Patient 1’s dysphagia is caused by global inefficiency of swallowing for foods and liquids.
On the other hand, the second patient (Patient 2), had 180 days of posttreatment follow-up. Patient 2 achieved an 89% improvement in SSQ Total Score, with an 84% improvement in the SSQ sub-score the necessity of repeat swallows during consumption. Benitec pointed out that Patient 2’s average post-dose SSQ Total Score of 82 constitutes normal swallowing. Frequency of low-volume sequential swallows, evaluated via VFSS, also showed a 92% reduction after treatment with the gene therapy. As in Patient 1, comparisons were measured with reference to the Patient 2’s average values for visits during the NH study. The company noted that Patient 2’s dysphagia is driven by pathologic low-volume sequential swallowing.
Both Patient 2 and Patient 1 were treated with the study’s low dose of BB-301, 1.2x1013 vg/subject. No significant adverse events were reported. It was noted that Patient 1 had more severe symptoms at baseline than Patient 2.
“We are grateful to the subjects and their families for their strong support and continued participation in the BB-301 clinical development program,” Jerel A. Banks, MD, PhD, the executive chairman and CEO of Benitec Biopharma, said in a statement.1 “We are highly encouraged by the significant, clinically meaningful improvements observed for both subjects treated at the low-dose of BB-301, with Patient 2 achieving a clinically normal swallowing profile based on the results of the SSQ. The third patient will be treated with the low dose of BB-301 this month, and we are optimistic about the potential for continued benefit in subjects enrolled in the ongoing study. We look forward to enrolling additional subjects at the next, higher doses of BB-301 in 2025.”
Benitec’s investigational new drug application for BB-301 was originally cleared by the FDA in June 2023.2 BB-301 is based on the company’s DNA-directed RNA interference (ddRNAi) platform and consists of a bifunctional construct that expresses a codon-optimized copy of the Poly-A Binding Protein Nuclear-1 gene (PABPN1) and 2 small inhibitory RNAs (siRNAs) that are modeled into microRNA backbones with the intention of silencing expression of mutant PABPN1; it is delivered via a novel AAV9 vector. In addition to the potential benefits of providing a functional copy of PABPN1, Benitec Biopharma expects that BB-301 will improve atrophy and muscle weakness by reducing the build-up of insoluble mutant PABPN1.2,3 The first patient in the trial was dosed in November 2023.4
“We are deeply appreciative of the unwavering dedication of the clinical research team at our US clinical trial site, our clinical and scientific research advisors in France, and our specialist speech language pathology research advisors in Canada, all of whom have guided the evolution of our understanding of the natural history of OPMD and our implementation of the ideal processes and procedures to facilitate the conduct of the initial clinical evaluation of BB-301,” Banks said in a statement in November 2023.4 “Today we have taken a critical step towards the clinical validation of our Silence and Replace-based approach to the management of genetically defined disorders, and our central goals remain focused on the improvement of the lives of patients suffering from OPMD.”
