Objective
We propose a Pilot clinical trial to evaluate the safety, tolerability and preliminary efficacy of allogenic islet transplant under the anterior rectus sheath (ARS) with and without gastrin treatment. Participants will be followed for 1 year. Outcomes of ARS IT will be compared to outcomes of COH’s intraportal IT with and without gastrin. Objectives include:
1. To determine the safety and tolerability of deceased donor islet transplant/s under the anterior rectus sheath. Participants will be closely monitored for adverse events with comprehensive clinical laboratory test results, vital signs, physical exam and imaging (ultrasound, MRI). Special focus will be given to assessment of the anterior abdominal wall for signs of infection or inflammation. All AEs will be graded for severity and attribution to the IT procedure, islet product, GAST-17, immunosuppression and other study medications will be determined. Incidence and severity of AEs, with a focus on those related to the IT procedure such as pain, bleeding, thrombosis, gut injury, wound infection or subsequent hernia, and increased liver enzyme levels will be compared to those reported in COH’s other intraportal IT protocols and published reports. MRI assessments allow us to monitor the islet graft under the ARS, but also to assess the liver for the development of fat deposition in liver, which has been reported in 20% of intraportal IT recipients. We expect that transplant to the ARS will be associated with fewer adverse effects than intraportal islet transplant.
2. To evaluate the preliminary efficacy of deceased donor islet transplant/s under the anterior rectus sheath. Efficacy of ARS IT will be evaluated for one year post the last IT based on the primary and secondary efficacy endpoints established under COH’s other clinical IT trials. These include outcomes beyond A1c. The primary efficacy endpoint will be the proportion of subjects achieving a composite endpoint of insulin independence, freedom from severe hypoglycemia, and a HbA1c ≤ 6.5% at 1 year post last IT (complete response). A secondary efficacy endpoint will be the proportion of subjects who are free of severe hypoglycemic episodes (SHE) and have a HbA1c ≤ 7.0% (partial response). This was the primary efficacy endpoint used to define islet transplant success under the Collaborative Islet Transplant -07, Phase III, (CIT) multicenter islet transplant alone trial and will allow us to compare rates of success with those published from the CIT. Additional efficacy data will include assessment of the following post-transplant: C-peptide response (a marker for insulin secretion), percent reduction of daily insulin use per 100,000 IEQ, change from baseline of HbA1c, change in glucose time in range (70-180 mg/dl) and time in tight range (70-140 mg/dl) during continuous glucose monitoring, incidence of hypoglycemia, and diabetic ketoacidosis monitoring per T1D Outcomes Program definitions, and other patient-reported outcomes such as general health and diabetes-related quality of life. Efficacy outcomes in recipients of ARS IT with GAST-17 will be compared to ARS IT alone and with recipients of intraportal IT with the same immunosuppressive induction with and without GAST-17 treatment. Outcomes will be analyzed for non-inferiority.
3. To characterize differences in exploratory biomarkers of IT function, survival, allo- and autoimmune response at the anterior rectus sheath site. To assess transplant site impact on islet engraftment, islet injury, and immune response, participants will undergo serial assessment of COH’s standard battery of IT biomarkers, including genomic markers of islet injury (donor cell free DNA) and whole-body responses genomic marker (cell free RNA conducted by Romix Biosciences), auto- and allo-immune antibodies, and immune cell phenotyping. We anticipate that ARS IT will be associated with less instant blood mediated inflammatory reactions, graft injury, and immune response, as compared to intraportal IT.
Background Rationale
This project will examine islet transplant outcomes in adults, age 18-68, who have difficult to control Stage 4 T1D >5 years with undetectable C-peptide and complicated by frequent, severe hypoglycemia and hypoglycemia unawareness. People with T1D at this stage no longer have beta cell function and do not benefit from other approaches aimed at protecting and preserving residual beta cell mass. Thus, beta cell replacement is best suited to address glucose lability and reduce burden of constant disease self-management. The potential risks of immunosuppression are balanced in the setting of severe hypoglycemia and glucose lability, which is associated with premature mortality.
Ongoing challenges with the intraportal IT site, need for a retrievable graft site to support safer application of emerging stem-cell based beta cell replacement strategies, and promising evidence of success in the anterior rectus sheath (ARS) warrants further evaluation in the setting of well-characterized deceased donor IT. The hope is that further validation of the ARS as a transplant site will support safe advancement of allogeneic and emerging hypoimmune stem-cell derived IT approaches, so that beta cell replacement can be made more broadly available to people with T1D at every age and stage.
This project involves treatment with two COH investigational products: 1) Human allogenic islet cells: COH has sponsored an Investigational New Drug Application (IND) with the FDA for deceased donor-derived human allogenic islets since 2001 and conducted multiple clinical IT trials. There are more than two decades of strong evidence supporting the safety and efficacy of islet transplant by our group and others, 2) Gastrin-17 (GAST-17): COH is also sponsor of an investigational gastrin analogue, GAST-17, as an adjunct treatment for T1D IT recipients under our allogenic islet transplant IND (BB-IND 9988). The rationale for using gastrin to enhance beta cell mass and function after IT was based on pivotal in vitro and in vivo studies that demonstrated that gastrin stimulated beta cell expansion, augmented beta cell function and reduced beta cell-directed inflammation. Pentagastrin (Peptavlon) which was used to diagnose medullary carcinoma of the thyroid was withdrawn from the market but not for reasons of safety. Transition Therapeutics, Inc. (Toronto, Canada) conducted clinical studies using an investigational gastrin analogue combined with epidermal growth factor-1 analogue for treatment of diabetes. The treatment was well-tolerated, improved HbA1c, and reduced daily insulin requirements (personal communications). COH proceeded to develop its own cGMP-quality gastrin analogue product, [Leu15] Gastrin-17 Analogue (GAST-17), under its existing biologics IND for IT (BB-IND-9988). GAST-17 is a synthetic terminal peptide of human gastrin hormone with enhanced stability. GAST-17 was shown to be biologically equivalent to endogenous human gastrin. It was synthesized at Bachem (Torrance, CA). The product was lyophilized, vialed and qualified at the COH GMP facility, and is requalified for stability annually. GAST-17 is administered subcutaneously twice daily for 30 days. GAST-17 has been well-tolerated with no associated serious adverse events and no early discontinuations. The most observed symptoms were heartburn, nausea, and vomiting that were resolved with over-the-counter antacids, proton pump inhibitor, and/or Zofran.
Description of Project
The front of human body has a pair of muscles extending from the chest cage to the pelvis called rectus muscles. They protect the internal organs in the abdomen and aid with the spine bending forward. Each of these muscles is covered with a protective sheath and help coordinate its movement. Part of the blood drainage from these muscles goes into the liver through the same network of veins that collect blood from the pancreas and intestine. Placing the islets underneath the sheath covering the rectus muscle is a viable alternative site to the liver for islet transplant (IT) as demonstrated in non-human primates and in one person with T1D who received stem-cell derived islets and achieved insulin independence for more than a year. Key advantages of this site are that it is self-contained, permits minimally invasive procedure for injection of islets, and can allow for the potential graft imaging and retrieval, particularly important if tumor formation were to occur in a post-stem cell transplant. This is increasingly important as gene-edited islets advance, which could further increase the potential for tumor development because of gene alteration. Also, placing he islets in this site could avoid the high level of inflammation and islet death that happens when transplanted islets are exposed to high volume of recipient blood, high glucose, fat and drug levels as it occurs in the liver. This could support greater islet engraftment, survival, and long-term function from a single infusion. Thus, this clinical study will test if the safety and functionality of islets transplanted to the rectus muscle sheath is as effective as islets transplanted to the liver, in 7 adults with type 1 diabetes for more than 5 years and are experiencing frequent and sever episodes of low blood sugar. Each will receive one or two IT, followed medically for one year from the last transplant, and the diabetic metabolic control of these subjects will be compared with others who received their islet transplant directly into the liver. Some of treated subjects under this clinical trial will also receive one month treatment with a hormone called Gastrin given as two under the skin injections each day in a similar manner to injection of insulin. Gastrin injections in another ongoing trial show enhanced protection and an earlier function of transplanted islets as well as achieving insulin independence with lower number of transplanted islets. Results of this trial will be compared to other liver transplanted islet trials.
Anticipated Outcome
Establishment of a viable extrahepatic site for IT can support better islet engraftment and long-term function without the high fractional graft loss due to IBMIR. It is also critically needed to support safe transplantation (and retrieval if needed) of stem cell derived islet products, particularly with advancing gene edited islets which may be associated with greater risk of tumorigenicity. IT under the ARS is less invasive and can be easily imaged with standard imaging technologies such as ultrasound or MRI and can be retrieved if untoward differentiation of remnant stem cells happened and deemed risky. It may also allow for better long-term survival of islets without exhaustion due to less glucose and fat toxicity and less exposure to high immune suppression drug levels and their negative impact on insulin secretion as compared to intraportal islet transplant. The anterior rectus sheath was found suitable in NHP studies and in the setting of clinical autologous iPSC transplantation. This pilot trial will deliver the first comprehensive evaluation of the anterior rectus sheath as potential site of allogenic IT. The study design allows for outcomes to be directly compared to those of intraportal IT, where the target islet dose and safety and efficacy are supported by decades of data. Positive outcomes of this initial pilot study will provide preliminary safety and efficacy data to support larger scale clinical trials with donor-derived or SC-derived islet transplants. Future clinical trials could also combine ARS transplant site with other islet protective approaches funded by Breakthrough T1D that aim to further reduce the required islet mass or improve the safety and efficacy of immune suppression agents such as with the use of anti CD40 to replace tacrolimus as a long-term immune suppressing agent. This project is in direct alignment with Breakthrough T1D’s Project ACT, which is focused on accelerating cell therapies for people with T1D.
Relevance to T1D
Type 1 diabetes is a chronic disease, and with time there is tendency for deterioration of metabolic control and loss of hormonal and neurologic manifestation of low blood sugar (hypoglycemia) increasing the risk for adverse events such as the inability to think or act properly, needing assistance from others and even seizure or comma. Presence of functional insulin producing cells in the body of individuals with T1D has been shown to help stabilize blood glucose and reduce frequency or eliminate episodes of hypoglycemia and associated risks.
Research strongly supports the safety and efficacy of deceased donor islet transplantation (IT) to reduce/eliminate severe episodes of low blood glucose, stabilize overall glycemic control, induce insulin independence, and improve the quality of life in adults with type 1 diabetes (T1D) complicated by severe hypoglycemia or already immunosuppressed for renal transplant. Intraportal transplant of islets into the liver is the primary site used for clinical transplantation. However, the intraportal route has issues including a risk of bleeding and vascular injury, lack of adequate oxygen supply, and instant blood-mediated inflammatory reactions (IBMIR) that result in substantial immediate loss of islets. Further, the high glycemic and toxic levels of the liver induce beta cell stress leading to islet exhaustion and the need for re-transplantation. In individuals with T1D, engineered human embryonic and adult stem cell-derived islets have restored insulin. Currently, we do not have long-term data on stem cell derived islets transplanted in the liver. The presence of undifferentiated induced pluripotent stem cells (iPSCs) in the final product raises safety concerns about placing these cells in the portal circulation, where they would be essentially impossible to remove in case of de-differentiation and tumor formation.
Placing the islets underneath the abdominal rectus muscle sheath is a viable alternative site for islet transplantation with preclinical feasibility demonstrated in non-human primates and one person with T1D who received own stem-cell derived islets achieving insulin independence for more than a year. Thus, the work proposed in this application aims at testing the feasibility of using this site as an alternative to the liver to house and protect donor derived islets and set the stage for its future use as a site for future stem cell derived islets with or without gene editing. This will expand the utility of natural and synthetic islets in patients with type 1 diabetes.