Subjects who have enrolled in the oculopharyngeal muscular dystrophy (OPMD) natural history study (Study BNTC-OPMD-NH-001) and have completed at least 6 months of follow up in Study BNTC-OPMD-NH-001 may be eligible to participate in this study, where all subjects will be treated with a single dose of BB-301. BB-301 will be injected directly into the middle pharyngeal constrictor muscle and the inferior pharyngeal constrictor muscle of the throat through the use of an open surgical procedure conducted under general anesthesia. The primary objectives of the 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.
Subject was previously enrolled in the BNTC-OPMD-NH-001 natural history (NH) study and completed at least 6 months of follow-up in the NH study.
Signed written informed consent prior to the initiation of any study-specific procedures.
Males or females, aged ≥50 to ≤65 years at the time of NH study enrollment, with genetically diagnosed heterozygous OPMD disease (as indicated by 1 of the following allelic classifications: GCN10/GCN12, GCN10/GCN13, GCN10/GCN14, GCN10/GCN15, GCN10/GCN16) OR
Males or females, aged ≤65 years at the time of NH study enrollment, with genetically diagnosed homozygous OPMD disease (as indicated by 1 of the following allelic classifications: GCN12/GCN12, GCN13/GCN13, GCN14/GCN14, GCN15/GCN15, GCN16/GCN16).
Subject has received prior treatment with an adeno-associated virus (AAV) vector (e.g., AAV-based therapy for the treatment of hemophilia B [including HEMGENIX®], AAV-based therapy for the treatment of RPE65 mutation-associated retinal dystrophy [including LUXTURNA®]).
Subject with presence of anti-AAV9 antibody titers >1:50.
Subject is pregnant or breastfeeding.
In the investigator's opinion, the subject's pharyngeal muscle is not amenable to intramuscular (IM) injection due to clinically significant atrophy as assessed by maximum pharyngeal dilation for OPMD subjects (determined by normalized post-swallow hyoid rest pharyngeal area [HRAN] using videofluoroscopy) compared to relative HRAN measurements of pharyngeal dilation from a database comprising healthy control subjects as determined during the Screening Visit of the NH study.
Single group
BB-301: Dose escalation phase 1b cohort 1
GeneticBB-301 is composed of an AAV9 capsid, AAV9PL, which delivers the gene of interest, comprised of a recombinant genome encoding a single RNA transcript that produces a codon-optimized, wildtype PABPN1 protein as well as 2 short hairpin (sh)RNAs directed against the disease-causing mutant PABPN1 gene. Subjects in cohort 1 in the dose escalation phase of the study will receive a fixed number of intramuscular (IM) injections of BB-301 into the respective pharyngeal constrictor muscles on the day of dosing, with a total dose of 1.2e13 vg/subject.
BB-301: Dose escalation phase 1b cohort 2
GeneticBB-301 is composed of an AAV9 capsid, AAV9PL, which delivers the gene of interest, comprised of a recombinant genome encoding a single RNA transcript that produces a codon-optimized, wildtype PABPN1 protein as well as 2 shRNAs directed against the disease-causing mutant PABPN1 gene. Subjects in cohort 2 in the dose escalation phase of the study will receive a fixed number of IM injections of BB-301 into the respective pharyngeal constrictor muscles on the day of dosing, with a total dose of 1.8e13 vg/subject.
BB-301: Dose escalation phase 1b cohort 3
GeneticBB-301 is composed of an AAV9 capsid, AAV9PL, which delivers the gene of interest, comprised of a recombinant genome encoding a single RNA transcript that produces a codon-optimized, wildtype PABPN1 protein as well as 2 shRNAs directed against the disease-causing mutant PABPN1 gene. Subjects in cohort 3 in the dose escalation phase of the study will receive a fixed number of IM injections of BB-301 into the respective pharyngeal constrictor muscles on the day of dosing, with a total dose per subject to be determined following the completion of cohort 1 and cohort 2.
BB-301: Dose expansion phase 2a
GeneticSubjects in the dose expansion phase of the study will receive a fixed number of IM injections of BB-301 into the respective pharyngeal constrictor muscles on the day of dosing, at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D).
Incidence of dose-limiting toxicities (DLTs) in phase 1b
A DLT will be defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0, as follows: • Any Grade 2 toxicity not resolving within 14 days or any Grade 3 toxicity, assessed to be possibly related to the investigational product.
Incidence of adverse events (AEs) according to NCI CTCAE v5.0 in phase 1b and in phase 2a
For this outcome measure, AEs arising in the 360 days following administration of BB-301 will be considered. Long term AEs will be monitored for 15 years following subject dosing.
Phase 1b: Swallowing efficiency as measured by Vallecular Residue %(C2-4)^2
Pharyngeal residue in discrete anatomical locations will be assessed by applying a method that uses a common reference area across all residue locations, with residue area expressed as a percentage of the squared C2-C4 length reference scalar. The Analysis of Swallowing Physiology: Events, Kinematics and Timing (ASPEKT) method will be used to determine Vallecular Residue %(C2-4)\^2.
Phase 1b: Swallowing efficiency as measured by Pyriform Sinus Residue %(C2-4)^2
Pharyngeal residue in discrete anatomical locations will be assessed by applying a method that uses a common reference area across all residue locations, with residue area expressed as a percentage of the squared C2-C4 length reference scalar. The ASPEKT method will be used to determine Pyriform Sinus Residue %(C2-4)\^2.
Phase 1b: Global swallowing function as measured by the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale
The DIGEST scale is a validated 5-point Common Terminology Criteria for Adverse Events-compatible modified barium swallow grade, based on the interaction of pharyngeal residue and laryngeal penetration/aspiration ratings. DIGEST uses 2 component scores to quantify pharyngeal bolus transit: 1) safety profile (i.e., penetration/aspiration); and 2) efficiency profile (i.e., residue). Higher scores are indicative of more severe dysphagia, with 0 = no dysphagia, 1 = mild dysphagia, 2 = moderate dysphagia, 3 = severe dysphagia, and 4 = life-threatening dysphagia).
Phase 1b: Swallowing efficiency as measured by the Normalized Residue Ratio Scale (NRRS)
The NRRS is a continuous measurement for capturing residue severity using pixel-based measurements during videofluoroscopy that incorporate the ratio of residue relative to the available pharyngeal space and the residue proportionate to the size of the individual. "Pharyngeal residue" is a medical term used to describe material that remains in the pharynx post-swallow and is considered a sign of swallowing impairment. Pharyngeal residue collects most commonly in: 1) the valleculae, bilateral spaces between the base of the tongue and the epiglottis (measured by the NRRSv); and 2) the pyriform sinuses, spaces formed on either side of the pharynx between the fibers of the inferior pharyngeal constrictor muscle and the sides of the thyroid cartilage and lined by orthogonally directed fibers of the palatopharyngeus muscle and pharyngobasilar fascia (measured by the NRRSp).
Phase 1b: Pharyngeal constrictor muscle function as estimated by the Pharyngeal Constriction Ratio (PCR)
The PCR was created to quantify the efficiency of the pharyngeal phase of swallowing via videofluoroscopy and was demonstrated to be a surrogate for pharyngeal muscle strength. The PCR is a pixel-based measure made on lateral view videofluoroscopy swallow study frames. The PCR is calculated by tracing the unobliterated area of the pharynx (including the bolus) at the point of maximum constriction during the swallow and then dividing that area by a corresponding area measure when the pharynx is at rest.
Phase 1b: Maximum pharyngeal dilation as estimated by %(C2-4)^2-normalized post-swallow hyoid rest pharyngeal area (HRAN)
Maximum pharyngeal dilation will be estimated by HRAN. The post-swallow hyoid rest is defined as the earliest frame in videofluoroscopic swallowing study recordings following upper esophageal sphincter closure when the hyoid was observed to have descended and moved posteriorly to reach its original, pre-swallow position. The HRAN is the normalized (by %\[C2-4\]\^2) area on the frame of post-swallow hyoid rest.
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