Model TZ 102 -Fucosylates Hematopoietic and Progenitor Stem Cells

While TZ 102 is an off-the-shelf product, available to be sold directly to cancer centers, worldwide, for TIL therapy use, TZ 102 can also be introduced into the centralized manufacturing of T-cells. Studies show that TZ 102 enhances T-cell functionality without impacting T-cell viability or functionality.

TZ 102 TIL treatment will be developed and conducted, initially, at ‘bedside’, with no incremental staff or equipment required. The process is rapid and simple, requiring only a lab technical to draw the enzyme and GDP fucose into a syringe, inject TZ 102 into the bag of expanded TILs, and incubate the TILs with TZ 102 for thirty (30) minutes, at room temperature, whereupon the TZ 102 TILs are infused into the patient through an IV.

Our lead product, TZ101, is currently entering a registration trial for the prevention of infections under a Special Protocol Assessment (SPA) in allogeneic stem cell transplantation (Allo-SCT) in patients with leukemia, lymphoma, and other blood cancers who are eligible for transplant using cord blood. Today, the mortality rate from this procedure is high, with approximately 50% of patients receiving a stem cell transplant dying within one year post-transplant. A large number of these deaths are treatment-related and not directly cancer-related, either from infections or Graft vs Host Disease (GvHD) which, account for 40% of deaths. Infections stem from poor or delayed engraftment. GvHD manifests itself when immune cells from the donor attack the patient’s normal cells.

The company is also planning on initiating a label expansion focused phase 2/3 trial in the prevention of chronic GvHD patients receiving stem cells from peripheral blood.  This trial will address an additional cohort of patients receiving Allo-SCT, and combined with the population from the phase 3 trial will address a significant unmet medical need and large market.  TZ-101 has received orphan indication for these two indications.

We have complete a Phase 2 study at MD Anderson Cancer Center investigating the safety and efficacy of TZ 101 in reducing the time to engraftment and the incidence of infections in patients with hematologic malignancies who were candidates for dual-cord blood transplantation (Dr. EJ Shppall, principal investigator).  Other study endpoints included graft failure rate, GvHD incidence and survival at 100 days post-transplant (interim analysis publication:  U. Popat, Blood, 2015, vol. 125, number 19) TZ101 demonstrated a good safety profile with no observed infusion-related adverse events or adverse events considered related to TZ101.

Outcomes in engraftment, hematopoietic recovery, and infections:

Treatment of cord blood with TZ101 led to 1) a reduction in the time to neutrophil recovery with a median of 18 days compared to an historical control value of 26 days, 2) a reduction in the time to platelet recovery with a median of 35 days compared to historical matched control value of 49 days and 3) a reduced graft failure rate (5% versus 16% in historical controls).  Consequently, a significant clinical benefit was observed as the number of infectious episodes (viral, bacterial and fungal) in the TZ101-treated patient population was reduced by more than 65% (see graph below) and the 100-day survival rate was increased by 20% (77% as opposed to 64% in the historical controls).

While there was no difference in acute GvHD incidence in both patient groups, there was a marked and significant 4-fold reduction in chronic GvHD in the TZ101-treated patient group (5% vs 22% in the historical control group/see graph below).  Acute and chronic GvHD occur at different time periods post transplantation and also present different characteristics.

Based upon the results generated from our Phase 1/2 study showing the clinical benefits of TZ101 in reducing infections and chronic GvHD, we are moving towards two registration trials in two distinct stem cell sources:  cord blood, under the FDA approved SPA, and peripheral blood from unrelated and related donors.  The latter source of stem cells represents today 75 of all allogeneic transplantations.

Regulatory T-cells or Tregs, have an immuno-suppressive action without the toxicities associated with the immunosuppressive drugs currently used. It has been shown that an elevated number of circulating Tregs post-transplantation is a positive prognostic biomarker on GvHD incidence and overall survival. Initial attempts to use expanded Tregs infused prior to stem cell transplantation have demonstrated efficacy in preventing acute GvHD, but require high numbers of cells that are difficult to reach without using a complex and long expansion process (up to 21 days). In various animal models, fucosylated Tregs have been shown to be up to 100 fold more potent than untreated Tregs (S. Parmar et al., Blood, 2015, vol 125, number 9)

In order to investigate the potential benefit of fucosylated Tregs to reduce acute GvHD, an initial Phase 1/2 pilot study is currently being conducted at MD Anderson Cancer Center. The primary objective of this study is to assess the safety of fucosylated Tregs and clinically validate their superior potency in the prevention of acute GvHD.