Become–9: A Phase 1/2 Dose Escalation and Expansion Study of be-101 for the Treatment of Adults with Moderately Severe or Severe Hemophilia B

Background:

Despite advances in treatment options for people with hemophilia B, significant unmet needs remain, notably disease and treatment burden. To overcome the limitations of available therapies, we developed BE-101, a first-in-class B cell medicine (BCM) comprised of expanded and differentiated B lymphocyte lineage cells that have been genetically engineered to express and secrete Factor IX (FIX). Participants’ B lymphocyte lineage cells are collected through leukapheresis, edited ex vivo using CRISPR/Cas9 in combination with AAV-mediated homology-directed repair to precisely insert a human F9 gene encoding full length FIX protein (activity-enhanced Padua variant) into the CCR5 safe harbor gene locus. The terminally-differentiated human plasma cell BCMs derived from these precision gene engineered cells potentially offer natural longevity (persisting for decades), the capacity to secrete high levels of protein, the ability to engraft without host preconditioning, and re-dosability, thus making them an attractive platform for durable and tunable therapeutic effects in adolescents and children as well as adults. A robust nonclinical data package including genome safety assessments as well as short and long-term in vivo studies was submitted as an Investigational New Drug (IND) application to the US FDA. The FDA cleared this application as well as later granted orphan drug designation for BE-101. The initial clinical trial is planned to initiate later this year.

Study Design and Methods:

The BeCoMe-9 Study (Study BE-101-01) is a Phase 1/2, first in human, multi-center, open-label, dose-escalation study to evaluate the safety and clinical activity of a single intravenous (IV) dose of BE-101 in adults with moderately severe or severe Hemophilia B (<2 IU/dL FIX). Once infused, BE-101 is designed to engraft and continuously secrete FIX into the circulation to restore clinically meaningful levels of functionally active FIX.

The study includes 2 distinct parts: part 1 and part 2. In part 1, an ascending-dose design will be utilized to enable evaluation of increasing doses in a stepwise manner with the first dose level planned to target FIX activity above 1%. The objective for this dose escalation is to identify the dose of BE-101 required to achieve FIX activity at or above 15% of normal activity 28 days after infusion while also minimizing the number of participants who are potentially exposed to subtherapeutic or unsafe doses. Upon identification of a safe and efficacious dose in part 1 an expansion phase (part 2) will initiate. The initial cohort in the Part 2 expansion (Part 2a) phase will include up to 6 adult participants to further characterize the safety and activity of BE-101 at the selected dose. Further cohorts to evaluate BE-101 both in adolescents and in a multiple dose setting are also planned

Up to 24 participants will be enrolled across Part 1 (up to 18) and Part 2a (up to 6). Consented participants will complete a screening period to assess eligibility and upon enrollment will undergo leukapheresis collection to support BE-101 manufacturing. Following administration, participants are monitored for safety and clinical activity. The total duration of study participation is approximately 52 weeks (1 year) post IV administration of BE-101. The study is expected to initiate enrollment in the first dose escalation cohort in the second half of 2024 (NCT: Pending).