On February 16, 2023 Vor Bio (Nasdaq: VOR), a clinical-stage cell and genome engineering company, reported clinical data from VBP101, its Phase 1/2a multicenter, open-label, first-in-human study of trem-cel (previously VOR33) in patients with acute myeloid leukemia (AML) (Press release, Vor BioPharma, FEB 16, 2023, View Source [SID1234627323]). In the first patient, trem-cel maintained hematopoesis through three cycles of Mylotarg (gemtuzumab ozogamicin), which was well-tolerated at the initial dose level of 0.5 mg/m2. A second patient has successfully received a trem-cel transplant and engrafted normally. These data were presented today by Miguel-Angel Perales, MD, Chief, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center in a late-breaking poster at the 2023 Tandem Meetings (Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR) in Orlando, FL.
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"These data continue to demonstrate the potential of trem-cel as a next-generation hematopoietic stem cell transplant, which could transform treatment for patients with blood cancers such as AML," said Dr. Eyal Attar, Vor Bio’s Chief Medical Officer. "We are also encouraged that a second patient successfully received a trem-cel transplant and look forward to learning more as we treat additional patients and dose escalate Mylotarg. In addition, we plan to file an IND for VCAR33ALLO, a novel allogeneic CAR-T treatment which we believe could be more efficacious than Mylotarg in combination with a trem-cel transplant."
Trem-cel Safety & Durability
Patient 1 maintained neutrophil and platelet counts approximately five months (147 days) after transplantation with trem-cel. Due to detectable measurable residual disease (MRD), Patient 1 was moved to other therapies following administration of the third dose of Mylotarg, subsequently relapsed, and remains on study for long-term follow-up.
Similar to Patient 1, Patient 2 successfully received a trem-cel transplant and showed robust cell recovery with neutrophil engraftment occurring at Day 11 and platelet recovery on Day 17. Trem-cel was well tolerated in both patients, with no related and no unexpected adverse events (AEs) reported.
No Hematological Toxicity Observed Through Repeated Doses of Mylotarg
In Patient 1, neutrophil and platelet cell counts were maintained following three sequential Mylotarg doses at 0.5 mg/m2. This suggests potential protection from Mylotarg-related hematotoxicity. The only AE observed possibly related to Mylotarg through dose 3 was low grade nausea and vomiting, a known side-effect of Mylotarg. Mylotarg first-dose pharmacokinetics revealed 0.5 mg/m2 achieved Cmax and AUC parameters equivalent to 1-2 and 4-5 mg/m2 accordingly, potentially due to the decreased CD33 antigen sink.
Evidence of Mylotarg Causing CD33-negative Donor Cell Enrichment
In Patient 1, CD33-negative donor hematopoiesis was enriched across hematopoietic cell types following Mylotarg administration. In addition, the CD33 deletion was observed in donor cells of myeloid and lymphoid origin which were both enriched following Mylotarg, suggesting that CD33 is expressed in early hematopoietic cells and that Mylotarg treatment enriches for edited donor cells.
Interest in enrollment in VBP101 continues to be strong with a high level of investigator enthusiasm at all nine study sites. The company is moving forward with dose escalation of Mylotarg per the 3+3 dose escalation schema in the protocol. The Company is also on-track to submit an IND in the first half of 2023 for VCAR33ALLO, a CAR-T therapy using allogeneic healthy donor-derived cells, which it intends use in combination with trem-cel as a Treatment System.
About AML
AML is the most common type of acute leukemia in adults and one of the deadliest and most aggressive blood cancers, affecting 20,000 newly diagnosed patients each year in the United States. Approximately half of patients with AML who receive a hematopoietic cell transplant (HCT) suffer a relapse of their leukemia, with two-year survival rates of less than 20%, and relapse rates are higher for patients with certain adverse risk features. The fragility of engrafted hematopoietic stem cells prevents treatment following transplant, giving the cancer a chance to return.
About the VBP101 Clinical Trial
VBP101 is a Phase 1/2a, multicenter, open-label, first-in-human study of trem-cel in participants with AML who are undergoing human leukocyte antigen (HLA)-matched allogeneic HCT. Trem-cel is an allogeneic CRISPR/Cas9 genome-edited hematopoietic stem and progenitor cell (HSPC) therapy product, lacking the CD33 protein. It is being investigated for participants with CD33+ AML at high risk for relapse after HCT to allow post-HCT targeting of residual CD33+ acute AML cells using Mylotarg without toxicity to engrafted cells. Participants undergo a myeloablative HCT with matched related or unrelated donor CD34-selected HSPCs engineered to remove CD33 expression (trem-cel drug product). Mylotarg is given after engraftment for up to four cycles. The primary endpoint is the incidence of successful engraftment, defined as the first day of 3 consecutive days of absolute neutrophil count (ANC) ≥500 cells/mm2 by day 28. Part 1 of this study is evaluating the safety of escalating Mylotarg dose levels to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose. Part 2 will expand the number of participants to evaluate the Mylotarg recommended Phase 2 dose. For more information, visit: View Source
About Trem-cel
Tremtelectogene empogeditemcel (trem-cel), formerly VOR33, is a genome-edited hematopoietic stem and progenitor allogeneic donor product candidate where CD33 has been deleted using genome engineering. Transplant with trem-cel is designed to replace standard of care transplants for patients suffering from AML and potentially other blood cancers. Trem-cel has the potential to enable powerful targeted therapies in the post-transplant setting including CD33-targeted CAR-T cells.