Objective
Our major objective is to perform the necessary PK/PD studies needed to support Akston in moving the antigen-specific immunotherapy, AKS-107 into clinical trials to prevent or delay T1D onset in at-risk (Stage 2) pre-diabetic participants. This will position AKS-107 for IND-enabling preclinical and clinical studies, as it is essential to first determine critical pharmacological and translational parameters.
Specifically, we will:
1) Define AKS-107 pharmacodynamics with respect to depletion of insulin-specific B lymphocytes.
2) Determine AKS-107 dosing parameters of disease efficacy in T1D-prone mice and associated changes in T cell (effector and regulatory) and antigen-presenting cell (APC) populations (B lymphocyte, DC).
3) Translate PD and MOA parameters of AKS-107 from the mouse to the human immune system using ex vivo immune cell cultures from at-risk T1D individuals.
Our long-term goal is to position AKS-107 as a monotherapy or as part of a combination therapy (e.g., after teplizumab treatment) in a pivotal Ph2 prevention/delay study with at-risk (Stage 2) subjects with insulin autoimmunity, the outcome of which would trigger a pharmaceutical partnership to conduct a registrational Ph3 study. In the short-term, Akston is actively planning IND-enabling preclinical studies that are expected to initiate in Q3-2025 from which the first-in-human Ph1/2 trial is expected to initiate in Q2-2026.
Background Rationale
Type 1 diabetes (T1D) results when immune cells decide to go rogue and destroy beta cells in pancreatic islets. B lymphocytes “talk” to T lymphocytes by “presenting” self-proteins from the pancreas, which convinces the T cells to morph into The Hulk and smash (kill) beta cells. Insulin is a key self-protein in T1D; insulin autoantibodies (produced by insulin-binding B lymphocytes) are a sign that B lymphocytes are convincing T cells to Hulk out and go after beta cells. Clinical trials deleting B lymphocytes or reprogramming T cells have been successful in preserving beta cell function, but their effects are only temporary. When the B or T lymphocytes come back, beta cell destruction continues. Sustaining these drugs for longer periods of time is not safe, because they indiscriminately impact B (or T) lymphocytes, even the cells that participate in protective immune responses (i.e., the responses that fight germs and cancer). Eliminating insulin-binding B lymphocytes so they can’t talk to T cells (but leaving “good” B lymphocytes alone) offers promise in blocking autoimmunity but preserving protective immunity.
T1D onset can range from infant to adulthood, likely driven at least in part by differences in the autoimmune response that develops. Increasing the arsenal of different immunotherapies available to treat T1D could allow for greater personalization of therapy in the future. This grant therefore focuses on the drug, AKS-107, that is designed to achieve this goal.
Mouse models facilitate access to immune cells in the pancreas and have taught us much of what we know about how T1D occurs. We will use our unique insulin autoimmunity-centric mouse model of T1D in which mice develop accelerated onset of diabetes compared to the conventional T1D mouse model. We will complete studies using this novel, highly aggressive T1D mouse model to zero in on how AKS-107 can act to limit the development of insulin autoimmunity in Aims 1-2.
Studying the immune cells that drive T1D in humans is complicated by the inaccessibility of the pancreas in living individuals. Aim 3 will therefore assay peripheral blood from at-risk T1D participants as a practical biospecimen to determine AKS-107 activity on human anti-insulin B lymphocytes.
Together, these studies will support future AKS-107 clinical trials aimed at developing safer immune-targeting therapies that are available for T1D prevention, and potentially treatment when combined with beta cell replacement therapy.
Description of Project
Type 1 Diabetes (T1D) is an autoimmune disease in which the immune system destroys insulin-producing beta cells of the pancreas, ultimately leading to dependence on injectable insulin therapy for life. For most T1D patients, it is difficult to achieve normal glycemic control even with frequent blood glucose measurements, strict diet control, careful determination of insulin dosage, and multiple daily insulin injections. Considering this unmet medical need, therapeutically arresting or reversing disease before substantial beta cell destruction occurs will be aggressively pursued in a collaborative manner by academic (Vanderbilt/Bonami and University of Colorado/Smith) and biotech (Akston/Zion, Alleva) organizations.
Most immunotherapeutic approaches have focused on targeting and destroying pathogenic T cells that are responsible for killing beta cells, either via broadly acting immunomodulatory drugs that effect large populations of T cells (at the cost of immunosuppression) or safer and more focused antigen-specific approaches that target only the few disease-relevant pathogenic T cells. However, evidence of the pathogenic role of insulin-specific B lymphocytes in T1D is emerging via non-obese diabetic (NOD) mouse studies and a human clinical trial in which treatment with broadly acting immunotherapeutics that deplete large B lymphocyte compartments showed slowing, arresting, or even reversal of diabetes. Data from mice and humans identify insulin-specific B lymphocytes as major antigen-presenting cells (APCs) that activate and drive the pathogenic insulin-specific T cells that destroy the insulin-producing beta cells. Successful antigen-specific technologies directly targeting B lymphocytes in T1D have not yet been described.
Akston Biosciences therefore developed a novel insulin fusion protein therapy (AKS-107) to intervene in at-risk, pre-diabetic subjects by targeting pathogenic immune cells while also creating immunological tolerance to the dominant T1D autoantigen, insulin, thereby lowering the chances of converting to diabetes. To date our team has:
1) Developed and initiated AKS-107 PK assays
2) Demonstrated AKS-107-mediated, selective deletion of insulin-specific B lymphocytes in mice
3) Confirmed AKS-107 does not modulate physiologic blood glucose regulation
4) Developed an assay that can determine the ability of AKS-107 to bind and remove insulin-specific B lymphocytes from human T1D blood samples
5) Shown in vitro reduction in insulin-specific T cell activation by AKS-107
6) Demonstrated significant and reproducible reduction in diabetes incidence in different strains of NOD mice
7) Developed a GMP master cell bank for producing AKS-107 with acceptable titers and purity
8) Been issued a patent application covering AKS-107 and closely related backup candidates
To position AKS-107 for IND-enabling preclinical and clinical studies, it is essential to first determine critical pharmacological and translational parameters in the following specific aims, which will be completed by Dr. Bonami (PI, Vanderbilt) and Dr. Smith (Co-PI, Univ. Colorado), in collaboration with Dr. Zion and Dr. Alleva (Akston).
• Aim 1 (Vanderbilt): Define AKS-107 pharmacodynamics with respect to depletion of insulin-specific B lymphocytes.
• Aim 2 (Vanderbilt): Determine AKS-107 dosing parameters of disease efficacy in T1D-prone mice and associated changes in T cell (effector and regulatory) and antigen-presenting cell (APC) populations (B lymphocyte, DC).
• Aim 3 (Univ. Colorado): Translate PD and MOA parameters of AKS-107 from the mouse to the human immune system using ex vivo cell cultures from at-risk T1D individuals.
Completing these aims will provide critical knowledge to conduct IND-enabling preclinical GLP toxicology studies planned for Q3-2025 and develop clinical biomarker assays for the first-in-human Ph1/2 trial is expected to initiate in Q2-2026.
Anticipated Outcome
Based on our current knowledge of how AKS-107 is designed and demonstrated to function, we expect to determine the precise serum levels of AKS-107 (i.e., via PK) associated with the precise degree of insulin-specific B cell depletion and de-activation of insulin-reactive T cells (i.e., PD measurements). We will improve our understanding of how AKS-107 can induce T cell tolerance via modulating APC function by insulin-specific B cells. Finally, we will translate the degree of depletion of insulin-specific B cells in mice to that in human blood samples from at-risk T1D individuals to enable development of accurate biomarker assays for clinical use. Outcomes of these aims will provide critical knowledge to conduct successful preclinical GLP toxicology studies and develop clinical biomarker assays for PhI/II studies.
Successful T1D clinical trials with positive outcomes often have heterogeneous results, with drugs working well for some individuals, and less well for others. The AKS-107 bioassays we will develop and validate will augment Akston’s planned clinical trials by increasing the depth with which changes to autoantigen-specific immune responses can be measured in clinical trial participants, to help mechanistically dissect clinical responders from non-responders. Such assays could be further applied to clinical trial studies of other drugs to detect favorable changes in insulin-binding B lymphocytes. Improved understanding of the immunologic changes that track with favorable clinical response to immunomodulatory drugs could:
1) Help refine participant selection to those individuals most likely to benefit from the drug, as determined by their baseline immune profile
2) Accelerate clinical trial evaluation (reducing trial length from years to months) by providing immune endpoints that can be assessed more rapidly than downstream measures of declining beta cell function
3) Provide mechanistic insight into participant response heterogeneity
Relevance to T1D
The insulin self-protein (“autoantigen”) is viewed as a dominant structural target that pathogenic immune cells (T and B lymphocytes) recognize, resulting in their coordinated destruction of beta cells. AKS-107 specifically targets and destroys insulin-reactive B lymphocytes, while leaving the “good” B lymphocytes that support protective immune responses alone. Because the involvement of such B lymphocytes in human T1D is easily measurable via blood levels of insulin autoantibodies, world-wide autoantibody screening programs will identify at-risk and pre-diabetic subjects who are candidates for preventative monotherapy with AKS-107. Indeed, an immunotherapeutic prevention approach has recently been FDA-approved for T1D, i.e., the T cell-targeting drug, teplizumab. This approval provides a regulatory path for development of safer and more tolerable therapeutic possibilities such as antigen-specific approaches like AKS-107. In addition, AKS-107 could also be used in combination with therapies like teplizumab. For example, a single course of teplizumab could elicit a one-time, hard “re-boot” of the immune system, followed by chronic maintenance therapy with AKS-107, a safer drug that could be used to prevent re-emergence of autoimmune cells that target the major T1D self-antigen, insulin. Outcomes from these studies could benefit at-risk T1D individuals. Beta cell transplant is another active area of T1D research, as this could be used to restore blood glucose regulation in people with existing, and potentially long-standing T1D. For beta cell transplant therapy to succeed, the new beta cells require protection from the immune attack that destroyed the person’s original beta cells. Thus, people with established T1D could also benefit from AKS-107, as it could complement beta cell transplantation therapy as a cure for T1D.