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A Study to Evaluate the Safety and Clinical Activity of Intramuscular Doses of BB-301 Administered to Subjects With Oculopharyngeal Muscular Dystrophy With Dysphagia
Bu Faz 1/2 (Phase 1/2) çalışma, okülofaringeal musküler distrofi (oculopharyngeal muscular dystrophy, OPMD) hastalarında tek doz BB-301 tedavisini değerlendiriyor. BB-301, genel anestezi altında yapılan açık cerrahi işlemle boğazdaki orta ve alt farengeal konstriktör kaslara doğrudan enjekte ediliyor; çalışmanın amaçları güvenliliği ölçmek, en uygun dozu belirlemek ve yutma güçlüğü (disfaji) belirtileri üzerindeki etkiyi tanımlamaktır. Çalışmaya, BNTC-OPMD-NH-001 doğal seyir çalışmasına katılıp en az 6 aylık takibi tamamlamış, 50-65 yaş arası kişiler alınıyor.
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Inclusion Criteria: * 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. Exclusion Criteria: * 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. * Subject has received a diagnosis of head and neck cancer at any time. * Subject has any history of neck irradiation. * Subject has undergone a major surgical procedure to the mouth or neck. Subject is eligible for enrollment with a past medical history of routine dental procedures, tonsillectomy, or adenoidectomy. * Subject has abnormal liver function (serum alanine aminotransferase or aspartate aminotransferase \>2.5 × upper limit of normal). * Subject is immunocompromised or is receiving immunosuppressant therapy. * Subject has evidence of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, psychiatric, neurologic, or allergic diseases (including drug allergies but excluding untreated, not clinically significant, seasonal allergies). * Subject has NCI CTCAE grade 3 hypertension defined as systolic blood pressure consistently ≥160 mmHg or diastolic blood pressure consistently ≥100 mmHg. * Subject has malnutrition defined as unintended weight loss of \>5-10% during the 1 to 6 months prior to Screening and a body mass index (BMI) of \<18.5 to 20 kg/m², or subject has cachexia defined as weight loss of \>5% over the past 6 months or a BMI of \<20 kg/m² and ongoing weight loss of \>2%. * Subject has received treatment with an investigational drug, investigational device, or approved therapy for investigational use within the 3 months or 5 half-lives prior to Screening. * Subject has any kind of disorder that, in the investigator's opinion, compromises the ability of the subject to give written informed consent and/or to comply with study procedures. * Subject is unwilling or unable to comply with study procedures and scheduled follow-up visits. * Subject has any other medical or social condition that, in the investigator's opinion, would not permit the subject to complete the study or sign informed consent.