A Study to Evaluate the Safety and Clinical Activity of Intramuscular Doses of BB-301 Administered to Subjects With Oculopharyngeal Muscular Dystrophy With Dysphagia

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.

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.

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.

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.

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 Other Pharyngeal 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 Total Pharyngeal Residue %(C2-4)^2.

Videofluoroscopy will be used to characterize the area of the pharynx at the point of maximum constriction during swallowing. The PhAMPC uses the videofluoroscopy frame of maximum pharyngeal constriction, defined as the frame with the smallest amount of unobliterated air space and barium-containing bolus visible in the pharynx. The pixelated area of the frame of maximum constriction is normalized via the use of the C2-C4 length squared (i.e., [C2-4]^2) as the denominator.

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 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 ASPEKT method will be used to determine 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 Other Pharyngeal 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 Total Pharyngeal Residue %(C2-4)^2.

Videofluoroscopy will be used to characterize the area of the pharynx at the point of maximum constriction during swallowing. The PhAMPC uses the videofluoroscopy frame of maximum pharyngeal constriction, defined as the frame with the smallest amount of unobliterated air space and barium-containing bolus visible in the pharynx. The pixelated area of the frame of maximum constriction is normalized via the use of the C2-C4 length squared (i.e., [C2-4]^2) as the denominator.

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).

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).

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.

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.

The CWDT is the time in seconds a subject requires to swallow 80 mL of ice-cold water.

The MSS is the time in seconds a subject requires to drink 150 mL of cold tap water as rapidly as possible.

The MSV is the maximum amount of room-temperature tap water a subject is able to consume in 1 swallow.

The SSQ is a self-report inventory assessing subjective symptoms of oropharyngeal dysphagia with strong content, construct, discriminant, and predictive validity and test-retest reliability in a range of patient populations. The SSQ is a 17-item questionnaire which was developed to measure symptomatic severity of oral-pharyngeal dysphagia as reported by the affected subject. The questionnaire uses a 100-mm long visual analogue scale for all but 1 question. Possible scores range from 0 to 1700, with higher scores indicating greater swallowing difficulty.

The IDDSI Functional Diet Scale is a subject-reported oropharyngeal dysphagia functional outcome scale intended to capture the severity of oropharyngeal dysphagia, as represented by the degree of diet texture restriction recommended for the subject. The IDDSI framework consists of a continuum of 8 levels (0-7), where drinks are measured from Levels 0-4, while foods are measured from Levels 3-7. The IDDSI framework provides a common terminology to describe food textures and drink thickness. Lower scores reflect diet texture restrictions to thin liquids.

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).

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).

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.

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.

The CWDT is the time in seconds a subject requires to swallow 80 mL of ice-cold water.

The MSS is the time in seconds a subject requires to drink 150 mL of cold tap water as rapidly as possible.

The MSV is the maximum amount of room-temperature tap water a subject is able to consume in 1 swallow.

The SSQ is a self-report inventory assessing subjective symptoms of oropharyngeal dysphagia with strong content, construct, discriminant, and predictive validity and test-retest reliability in a range of patient populations. The SSQ is a 17-item questionnaire which was developed to measure symptomatic severity of oral-pharyngeal dysphagia as reported by the affected subject. The questionnaire uses a 100-mm long visual analogue scale for all but 1 question. Possible scores range from 0 to 1700, with higher scores indicating greater swallowing difficulty.

The IDDSI Functional Diet Scale is a subject-reported oropharyngeal dysphagia functional outcome scale intended to capture the severity of oropharyngeal dysphagia, as represented by the degree of diet texture restriction recommended for the subject. The IDDSI framework consists of a continuum of 8 levels (0-7), where drinks are measured from Levels 0-4, while foods are measured from Levels 3-7. The IDDSI framework provides a common terminology to describe food textures and drink thickness. Lower scores reflect diet texture restrictions to thin liquids.