Tremtelectogene empogeditemcel or “trem-cel” (formerly VOR33)

Trem-cel genetically modifies healthy donor HSCs to remove the CD33 surface target

We are developing trem-cel as a Hematopoietic Stem Cell Transplant (HSCT) product candidate to replace the standard of care in transplant settings. Once trem-cel has engrafted, we believe that patients can be treated with anti-CD33 therapies, such as Mylotarg™ or our CAR-T therapy product candidates, with limited on-target toxicity.

We have initiated VBP101, a Phase 1/2a clinical trial in patients with CD33-positive AML who are at high risk of relapse. The primary goals of the trial are to evaluate tolerability and feasibility of the trem-cel stem cell transplant, with a focus on confirming that trem-cel can engraft normally.

Following engraftment, patients will be eligible to be treated with Mylotarg, a CD33-directed Antibody Drug Conjugate (ADC) therapy, in order to potentially prolong leukemia-free survival and provide evidence that trem-cel protects against the myelosuppression that typically accompanies treatment with Mylotarg.

CD33 targeted therapies

A number of biologics investigated by third parties as potential therapeutics in AML and other blood cancers have been based on targeting CD33, which is expressed, on average, in between approximately 85 to 90% of bulk AML patient samples and over 75% of leukemic stem cells. [Source: Perna, Sadelain, et al. Cancer Cell. 2017]

CD33 is an attractive target for the development of AML therapeutics based on preclinical and clinical results from third parties demonstrating the ability of anti-CD33 directed therapies to deplete tumor cells. [References: 1. Sievers EL, et al. Blood. 1999;93(11):3678-3684. 2. Stein EM, et al. Blood. 2018;131(4):387-396]

However, CD33-directed therapeutic approaches have had limited impact in improving the prognosis of patients with AML due in part to on-target toxicity. This on-target toxicity can have myelosuppressive effects, such as neutropenia, which is an abnormally low number of certain white blood cells, and thrombocytopenia, which is an abnormally low number of platelets.

The only CD33 targeted therapy approved by the FDA for the treatment of AML is gemtuzumab ozogamicin, which is marketed by Pfizer under the brand name Mylotarg. Mylotarg is an ADC that targets CD33 on AML cells and is designed to deliver a potent cytotoxin directly to tumor cells.

However, due to the expression of CD33 on a broad set of hematologic progenitor cells, Mylotarg not only attacks AML cells, but it also depletes healthy blood cells, including HSCs and other progenitor cells that express CD33. Primarily due to its toxicity profile, Mylotarg is currently used only in a limited setting, in both first line and relapsed/refractory disease.

Without a solution to the problem of CD33 on-target toxicity, we expect all CD33-targeted therapies to produce thrombocytopenia and neutropenia which may result in the same limited clinical utility as Mylotarg.

We believe engineering the patient to remove CD33 is a unique approach designed to protect from on-target toxicity and unlock the potential of CD33 as a therapeutic target. By removing CD33 expression in healthy cells, we expect to render these cells and their progeny treatment resistant to CD33-directed therapies, thereby providing robust protection from these therapies’ cytotoxic effects.

Trem-cel preclinical data

In preclinical studies, we observed the resistance of our eHSCs to Mylotarg. We used in vitro cytotoxicity assays to measure the effects of various concentrations of Mylotarg on HSCs and their progeny (collectively, “HSPCs”) that have differentiated into myeloid lineage cells. We tested both wild type cells whose CD33 surface targets had not been manipulated (“CD33WT”) and cells that we had genetically engineered to remove CD33 (“CD33Del”). We observed that CD33Del cells had an approximately 70-fold increase in IC50 in comparison to CD33WT cells and, as expected, observed few differences in cell killing at extreme Mylotarg concentrations. This was consistent with results from our in vivo studies.

Removal of CD33—no observed impact on biology

In addition to data generated by us, academic laboratories at Columbia University, the University of Pennsylvania, and the Fred Hutchinson Cancer Research Center have each conducted experiments in vitro and in vivo with very similar findings, showing that CD33 can be removed from HSCs without any deleterious impact on cell biology.

While these preclinical data offer encouraging evidence of the non-essential nature of CD33, we believe the strongest support for our approach comes from existing human genetics data. We have found 65 individuals with homozygous loss of function mutations in the CD33 gene using the genetic database maintained by the Broad Institute. More recently, we identified 176 individuals with homozygous loss-of-function mutations in CD33 through the database maintained by the UK Biobank. This critical evidence suggests the non-essential nature of CD33 function in humans, mitigating concerns associated with introducing CD33Del eHSCs in humans.

About the VBP101 clinical trial

We have initiated VBP101, our first-in-human Phase 1/2a trial of trem-cel in combination with Mylotarg.

Trem-cel has been granted Orphan Drug Designation and Fast Track designation from the U.S. Food and Drug Administration.

The VBP101 trial is actively enrolling patients. This trial will provide important validating evidence of the potential of trem-cel and our broader eHSC approach. Preliminary data on the first patient who received trem-cel was shared in December 2022 and additional updates are expected in 2023.

Trem-cel with other targeted therapies

Mylotarg is currently the only anti-CD33 therapy approved by the FDA. We believe that other anti-CD33 therapies that are not yet approved, such as our VCAR33 product candidates or bispecific antibodies, may ultimately be better targeted therapies due to higher expected potency and target specificity.

Different therapeutics may also be more suitable in various clinical settings and disease states. We therefore plan to support research and development efforts studying the benefits of trem-cel and other eHSC approaches with several targeted therapies using different treatment modalities with the intent of optimizing the potential for trem-cel and other eHSC programs to eventually become a new standard of care in transplantation, unlocking the potential of multiple targeted therapies for patients with AML and other blood cancers.

Trem-cel and Myelodysplastic Syndrome and Myeloproliferative Neoplasm

Other blood cancers overexpress CD33, including myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN). MDS consists of a spectrum of bone marrow cancers that are characterized by reduction in blood cell counts and an increase in immature blood cells in bone marrow.

This condition evolves into AML in up to 30% of cases. Similarly, MPNs are a group of blood cancers such as chronic myelogenous leukemia, chronic neutrophilic leukemia, polycythemia vera, primary myelofibrosis and essential thrombocythemia where excessive fully differentiated blood cells are produced by the bone marrow, and these conditions may also evolve into more aggressive AML. Patients with these conditions can be segmented into different risk categories based on cell counts and cytogenetics, with intermediate- or high-risk patients often treated with HSCT, and together MDS and MPN are the most common indications for allogeneic HSCT outside of AML. Scientific evidence produced by third parties shows that blast cells responsible for MDS and MPN express CD33 and other myeloid cell surface targets. We believe trem-cel has the potential to provide a therapeutic window that enables anti-CD33 therapies to be effective in those settings, and we are exploring the potential use of trem-cel in combination with targeted therapies in these indications.

Related Publications

Initial First-In-Human Results: CD33-Deleted Hematopoietic Stem and Progenitor Cells Display Normal Engraftment after Hematopoietic Cell Transplant (HCT) and Tolerate Post-HCT Gemtuzumab Ozogamicin (GO) without Cytopenias

In Depth Assessment of Off-target Editing by CRISPR/Cas9 in VOR33, an Engineered Hematopoietic Stem Cell Transplant for the Treatment of Acute Myeloid Leukemia

Rigorous Assessment of Off-Target Editing by CRISPR/Cas9 in VOR33, an Engineered Hematopoietic Stem Cell Transplant for the Treatment of Acute Myeloid Leukemia

Next In Our Pipeline

VCAR33ALLO (Allogeneic)