Objective
The primary objective of the planned phase 1 clinical trial for GNTI-122 is to assess the safety and tolerability of GNTI-122 with and without low dose rapamycin (to activate and provide a specialized growth signal to only the GNTI-122 cell product) in adult patients with recently diagnosed T1D. Safety is always the first objective when investigating a new therapy.
A secondary objective is to assess the presence and levels of GNTI-122 with and without low dose rapamycin and to assess the change in the patient’s ability to produce insulin over time in adult patients with recently diagnosed T1D. The study is not expected to be sufficiently powered to show statistically significant efficacy. The main goal is to show safety and immunomodulatory action (effects of GNTI-122 on disease causing autoimmune cells) in adults first, to enable transition into pediatric patient where C-peptide (a marker for insulin product) change will be a key readout. This secondary objective lets us know how well the engineered cells are doing in the patient and to see if they are having the intended action in helping to maintain insulin production.
There will be additional exploratory endpoints to tell us more about how well the cells are working. These include assessment of long-term safety and tolerability and other markers that indicate how well the GNTI-122 product is protecting the insulin producing cells of the body and halting the autoimmune attack on those cells. This will be measured by a variety of assays requiring blood draws from the patient to detect the impact of GNTI-122 on various blood cells, use of continuous glucose monitors and with patient reported outcomes like questionnaires, and diaries of insulin usage.
Background Rationale
In T1D, the body's immune system mistakenly attacks and destroys the insulin-producing cells in the pancreas. This happens because certain immune cells, called T effector cells (Teffs), become overactive and cause inflammation. Normally, another type of immune cell, called T regulatory cells (Tregs), keeps these Teffs in check and maintains balance in the immune system. However, in people with T1D, the Tregs don't work properly. They have trouble responding to a crucial signal (a protein called interleukin-2 or IL-2) that helps them survive and function. Because of this, the Teffs are not controlled and continue to attack the insulin-producing cells, leading to their destruction. For Tregs to be effective in treating T1D, they need to remain stable, get the IL-2 signal and specifically target the pancreas. This way, they can stay in the right place and suppress the harmful Teffs, reducing inflammation and protecting the insulin-producing cells.
Description of Project
T1D is a disease in which the body is unable to create sufficient insulin, a hormone that helps to regulate blood sugar levels. The planned clinical study will test an investigational cell therapy called GNTI-122 to learn if it can safely help the body maintain the ability to create insulin.
GNTI-122 is a unique drug cell therapy that is created from a participants own blood cells. For this study, a participant will undergo a procedure called leukapheresis to collect blood cells. GentiBio will use those blood cells to create the study therapy, which will be given back to the participant as a single dose about 4 weeks later.
GNTI-122 is an investigational cell therapy and is intended to help correct an imbalance of certain types of cells found in patients with Type 1 Diabetes (T1D). GentiBio plans to determine whether GNTI-122 can halt progression of early T1D, maintaining the body’s ability to create insulin.
Anticipated Outcome
This Phase 1 trial in recently diagnosed adult T1D, will have established GNTI-122’s safety and with some early evidence that it is working as intended to protect the insulin producing cells of the body. Additionally, we received feedback from the FDA at our pre-IND meeting, that our proposed endpoints would be sufficient to demonstrate the prospect of direct benefit and allow GentiBio to file an amendment to move GNTI-122 into the primary target population of recently diagnosed pediatric T1D patients. If GNTI-122 is successful in the clinic, it could effectively cure T1D in the target population by halting the immune attack. The durability of treatment will become clear as part of the clinical study but is anticipated to be on the order of years, possibly lifelong. Nonclinical studies in mice suggest the curative potential.
Relevance to T1D
Type 1 Diabetes (T1D) happens because certain immune cells, called T effector cells (Teffs), mistakenly attack and inflame the insulin-producing cells in the pancreas. Normally, another type of immune cell, called T regulatory cells (Tregs), keeps these Teffs in check to maintain balance in the immune system. However, in people with T1D, the Tregs don't work properly. They have trouble responding to a crucial signal (a protein called interleukin-2 or IL-2) that helps them survive and function. Because of this, the Teffs are not controlled and continue to attack the insulin-producing cells, leading to their destruction.
For Tregs to be effective in treating T1D, they need to specifically target the pancreas. This way, they can stay in the right place and suppress the harmful Teffs, reducing inflammation and protecting the insulin-producing cells. Additionally, Tregs that are specific to one antigen can also suppress immune responses against other antigens due to their colocalization. So far, Treg therapies for T1D have used patient-derived, polyclonal Tregs, which have not been very effective in maintaining tolerance and lack some critical components to work well. The GNTI-122 is designed to overcome the shortcoming of natural Tregs to halt the progression of T1D.