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Early Sustained Improvements in Oculopharyngeal Muscular Dystrophy Seen Through BB-301
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Additional interim clinical study results comprising 6- and 12-months of treatment data on multiple patients, is expected to be readout in the first quarter of 2025.
Jerel A. Banks, MD, PhD
New data from a single patient treated in a phase 1b/2a single-arm, open-label, dose-escalation study (NCT06185673) showed that treatment with BB-301 (Benitec), an investigational gene therapy, resulted in continued, sustained improvements in assessments of Total Pharyngeal Residue (TPR) and Subject-Reported outcome Instrument. BB-301, an agent in development for oculopharyngeal muscular dystrophy (OPMD), will have additional analyses of interim study data at upcoming medical conferences.1
BB-301, which has previously gained orphan drug designation by the FDA, is a novel, modified adeno-associated viral-9 (AAV9) capsid expressing a unique, single bifunctional construct promoting co-expression of both codon-optimized Poly-A Binding Protein Nuclear-1 (PABN1) and 2 small inhibitor RNAs against mutant PABPN1. The 2 siRNAs are modeled into microRNA backbones to silence expression of faulty PABN1, while allowing expression of the codon-optimized PABN1 to replace the mutant with a functional version of the protein.
At the 180-day post-dose assessment following the administration of a low-dose of BB-301, the treated patient showed meaningful reductions in average TPR values as compared with pre-dose average values during the OPMD Natural History Study. TPR was objectively characterized in via the completion of videofluroscopic swallowing studies which evaluate the complete swallowing process for each subject in the context of 4 food types (thin liquid, moderately thick liquid, extremely thick liquid, and solid food.
At thin liquid of 5 mL, the patient showed a post-dose average TPR of 2.8% (SD, 2.6), which was nearly half of the 9-month, pre-dose observation period average of 4.9% (SD, 2.2) observed in the natural history study. For moderately thick liquid, the pre-dose average TPR was 18.2% (SD, 12.3) and the post-dose average TPR was 10.0% (SD, 1.5) following treatment with BB-301. Similarly, for extremely thick liquid, treatment with BB-301 resulted in average TPR of 12.0% (SD, 0.1) after 6 months compared with the 9-month, pre-dose average of 21.5% (SD, 8.5). On solid food, the average TPR was 12.6% (SD, 0.4) following treatment vs 19.0% (SD, 10.3) for the 9-month, pre-dose observation period.
"We are pleased to report continued positive interim clinical study data for Subject 1 in the investigational assessments deemed to be most critical for the evaluation of clinical benefit by the KOLs in the fields of OPMD research and patient care,” Jerel A. Banks, MD, PhD, executive chairman and chief executive officer at Benitec, said in a statement.1 "Facilitating reductions in the quantities of solid food and liquid that remain in the throat post-swallow is believed to be a central indicator of improvement of swallowing and the reduction of the risk of aspiration in subjects suffering from OPMD."
He added, "Our second BB-301-treated subject was dosed in February 2024, and we are poised to dose the third subject in the third quarter of calendar 2024. We remain on track to report additional interim clinical study results (representing at least 6 or 12 months of follow-up for each study subject) on multiple patients in the first quarter of calendar 2025."
Investigators also reported 180-day post-dose average in Sydney Swallow Questionnaire (SSQ) total score, a paper-based outcome that measures the symptomatic severity of oral-pharyngeal dysphagia. After 6 months of treatment, the patient showed an SSQ total score of 820 (SD, 163), which was lower than the original 9-month pre-dose average score of 1136 (SD, 103). The therapy was also considered safe, with no serious adverse events recorded for the first 2 treated participants thus far. Notably, earlier this year, the company reported cases of gastroesophageal reflux disease or "GERD” as a result of treatment.
