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

NCT06185673 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: BNTC-OPMD-BB-301-01
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Oculopharyngeal Muscular Dystrophy

Outcome Measures

Primary Outcomes (12)

• 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.

  Up to 60 days

• 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.

  Up to 360 days

• 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.

  Baseline, Day 90, Day 180, Day 270, Day 360

• 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.

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 1b: Swallowing efficiency as measured by 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 Other Pharyngeal Residue %(C2-4)\^2.

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 1b: Swallowing efficiency as measured by Total 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.

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 1b: Pharyngeal constrictor muscle function as estimated by the pharyngeal area at maximum constriction (PhAMPC)

  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.

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 2a: 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 ASPEKT method will be used to determine Vallecular Residue %(C2-4)\^2.

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 2a: 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.

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 2a: Swallowing efficiency as measured by 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 Other Pharyngeal Residue %(C2-4)\^2.

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 2a: Swallowing efficiency as measured by Total 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.

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 2a: Pharyngeal constrictor muscle function as estimated by PhAMPC

  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.

  Baseline, Day 90, Day 180, Day 270, Day 360

Secondary Outcomes (18)

• Phase 1b: Global swallowing function as measured by the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 1b: Swallowing efficiency as measured by the Normalized Residue Ratio Scale (NRRS)

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 1b: Pharyngeal constrictor muscle function as estimated by the Pharyngeal Constriction Ratio (PCR)

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 1b: Maximum pharyngeal dilation as estimated by %(C2-4)^2-normalized post-swallow hyoid rest pharyngeal area (HRAN)

  Baseline, Day 90, Day 180, Day 270, Day 360

• Phase 1b: Dysphagia severity as measured by the cold water timed drinking test (CWDT)

  Baseline, Day 90, Day 180, Day 270, Day 360

Study Arms (1)

BB-301 Treatment

EXPERIMENTAL

The phase 1b component of the study is the dose escalation phase which will enroll up to 18 subjects in up to 3 dosing cohorts. The phase 2a component of the study is the dose expansion phase which will enroll up to 12 subjects.

Genetic: BB-301: Dose escalation phase 1b cohort 1; Genetic: BB-301: Dose escalation phase 1b cohort 2; Genetic: BB-301: Dose escalation phase 1b cohort 3; Genetic: BB-301: Dose expansion phase 2a

Interventions

BB-301: Dose escalation phase 1b cohort 2 GENETIC

BB-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 Treatment

BB-301: Dose escalation phase 1b cohort 3 GENETIC

BB-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 Treatment

BB-301: Dose expansion phase 2a GENETIC

Subjects 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).

BB-301 Treatment

BB-301: Dose escalation phase 1b cohort 1 GENETIC

BB-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 Treatment

Eligibility Criteria

• Age: Up to 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 is eligible and willing to undergo a surgical dissection of the pharyngeal region with intubation under general anesthesia to administer the study drug.
• Subject has moderate dysphagia, defined as pharyngeal area at maximum constriction (PhAMPC) \>2.7%(C2-4)\^2 with natural sips of thin liquid barium or PhAMPC \>2.1%(C2-4)\^2 with teaspoon delivery of moderately thick liquid barium.
• Subject is not of childbearing potential, i.e., is postmenopausal (absence of menstrual bleeding for ≥1 year before Baseline, without any other medical reason), or has documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy OR
• Subject or their partner is of childbearing potential and agrees to use 2 highly effective forms of contraception during the study and continuing through 52 weeks after the study drug administration. The 2 authorized forms of contraception are condom used with 1 of the following methods of contraception:
• bilateral tubal ligation
• combined oral contraceptives (estrogens and progesterone), vaginal ring, or implanted or injectable hormonal contraceptives with a stable dose for at least 1 month prior to the day of dosing; hormonal contraceptives must inhibit ovulation
• intrauterine device inserted at least 1 month prior to the day of dosing OR
• Subject agrees to abstain from heterosexual intercourse during study participation and to use a highly effective form of contraception (as described above) as backup if they become sexually active during the study. Abstinence is only acceptable if this is the subject's usual lifestyle. Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception.
• Subjects capable of donating sperm must agree not to donate sperm beginning at Screening and continuing through 52 weeks after the study drug administration.

You may not qualify if:

• 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.
• Subject with contraindication to the videofluoroscopy procedures (e.g., allergy to any of the radiopaque contrast agents planned for use in the study).
• Subject has received gene therapy (e.g., chimeric antigen receptor-positive T cell therapy for the treatment of leukemia, lymphoma, or multiple myeloma \[including ABECMA®, BREYANZI®, CARVYKTI™, KYMRIAH®, YESCARTA®, and TECARTUS™\], IMLYGIC® for the treatment of melanoma, SKYSONA® for the treatment of cerebral adrenoleukodystrophy, and ZYNTEGLO® for the treatment of β-thalassemia) within the 6 months prior to Screening.
• Subject for whom any of the proposed study procedures or medications (e.g., corticosteroids) would be contraindicated.
• Subject has had prior cricopharyngeal myotomy or cricopharyngeal botulinum toxin injection.
• Subject has had cricopharyngeal dilation within the 12 months prior to Screening.
• Subject with pre-existing clinically diagnosed and/or self-reported dysphagia has been hospitalized within the 12 months prior to Screening for treatment of pneumonia of nonpathogenic origin (e.g., aspiration pneumonitis secondary to aspiration of sterile gastric contents) or pneumonia secondary to bacterial pathogens. A subject is eligible for enrollment if diagnosed with pneumonia secondary to documented pathogenic organism(s)including: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, i.e., coronavirus disease 2019), non-SARS-CoV-2-related viral pathogens, and fungal pathogens.
• Subject has been intubated within the 30 days prior to Screening.
• Subject consumes a very restricted range of diet textures, defined as a score of ≤3 on the IDDSI Functional Diet Scale as determined during the Screening Visit of the NH study.
• Subject presents with muscular dystrophy and/or other neuromuscular diseases distinct from OPMD, or any other disease that may significantly interfere with the characterization of dysphagia in OPMD.
• Subject presents with other disorders associated with dysphagia, e.g., severe gastroesophageal reflux, esophageal stricture due to mechanical or chemical trauma, infection (e.g., esophageal moniliasis), drug-induced dysphagia (e.g., bisphosphonates), esophageal rings and webs, or spastic motility disorders of the esophagus.
• Subject with any concomitant illness likely to significantly decrease life expectancy or any malignancy other than curatively treated skin cancer or in situ carcinoma of the cervix, unless adequately treated or in complete remission for ≥5 years.

Sponsors & Collaborators

• Benitec Biopharma, Inc.: lead

Study Sites (1)

NYU Langone Health

New York, New York, 10016, United States

RECRUITING

MeSH Terms

Conditions

Muscular Dystrophy, Oculopharyngeal

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Milan R. Amin, M.D.

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jerel A. Banks, M.D., Ph.D.

CONTACT

(510)-780-0634; jbanks@benitec.com

Sophie Mukadam

CONTACT

smukadam@benitec.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 15, 2023
• First Posted: December 29, 2023
• Study Start: November 28, 2023
• Primary Completion (Estimated): November 1, 2030
• Study Completion (Estimated): November 1, 2040
• Last Updated: December 31, 2025

Record last verified: 2025-12

Locations

US (1)