Islet Transplantation Using PKX-001

Background

Clinical islet transplantation is today an accepted modality to treat selected diabetic patients with frequent hypoglycemic events and severe glycemic liability. Although islet transplantation outcomes have improved significantly in highly specialized centers with a 5-year insulin independence rate exceeding 50%, a proportion of patients require reintroduction of insulin later on. Tac may be partly responsible for the limited islet durability and the need for multiple donors for each recipient in spite of its ability to prevent rejection and autoimmune recurrence. In vitro studies of islets exposed to immunosuppressants have shown that Tac levels above 10-100 mg/L cause vacuolization and destruction of islets in culture.

Antifreeze proteins (AFPs) have generated considerable interest for their ability to protect cells under a variety of conditions. However, their large size restricts their use in medicine as they are unable to pass through capillaries into interstitial tissue and are unable to reach target cells.

With these disadvantages of AFPs in mind, Dr. Geraldine-Castelot-Deliencourt (Rouen, France) invented Antiaging glycopeptide, which is later manufactured by ProtoKinetix Inc. (St. Marys, West Virginia, US). ProtoKinetix' anti-aging glycopeptide, PKX-001, is a small, stable, synthetic replica of the larger, less stable AFP.

PKX-001 has gone through a series of tests in various outsourced laboratories in Europe and North America. These tests have proven its ability to protect a multitude of cell lines (Hela cells, adult fibroblast, neonatal fibroblasts, human neuronal stem cells, mouse neuronal stem cells, mouse islet cells, blood platelets, cluster of differentiation 34+ (CD34+) cells, and keratinocytes) against ultraviolet A (UVA), ultraviolet C (UVC), Hydrogen Peroxide, Inflammatory (ILβ), Time, Temperature (-196°C, -80°C, -3°C, 3°C, 4°C, 15°C and 22°C) and Low Serum induced cell death at pHs from 5.3 -10.5. In addition to protecting cell survival PKX-001 also preserves cell functionality. This has been tested via stem cell markers, CD34+ functionality tests, and in vivo studies where PKX-001 treated transplanted islet cells were found to reduce blood glucose concentrations in diabetic mice by 40% by day 40 in comparison to islet cells which were transplanted into mice without first being exposed to PKX-001.

In light of the beneficial roles of PKX-001 on cellular survival and functionality preservation, our team have evaluated the cytoprotective capacity of PKX-001 in islet transplant, especially its capacity of protection against the diabetogenic effect of Tac.

In vitro assessment of human islets in culture with PKX-001 supplementation has also showed enhanced quality and yield of post-preservation human islets and protection against acute exposure to Tac at clinical relevant doses compared with those without PKX-001 supplementation. Further analysis indicated that islets treated with PKX-001 had decreased oxidative stress, improved insulin release by increasing islet exocytosis, decreased islet loss during preservation due to apoptosis, even in the presence of Tac.

In vivo studies have complemented all in vitro findings above, which demonstrated that PKX-001 supplementation suppressed early inflammation and improved islet engraftment with long-term efficacy.

The proposed study is a phase I, non-randomized, open-label, single arm, prospective trial using retrospective controls.

Ten adult Islet transplant candidates (18 years and older), deemed appropriate for standard islet transplant at the University of Alberta Hospital will be enrolled in this investigation.

Retrospective data from 10 islet transplant patients consented for chart review (Protocol #: 000001120 entitled: "On-going review of islet transplant patients at the University of Alberta" and Protocol #: 000001122 entitled: "Collaborative Islet Transplant Registry") will be also collected.

The standard of Care controls will be identified from the Islet Transplant program database (period: 2014 - 2016) and anonymized by a simple numbering system.

Hypothesis:

Transplantation of PKX-001 treated islets is safe and improves graft outcomes.

Primary Objective:

To demonstrate safety of transplantation of PKX-001 treated islets.

Secondary Objectives:

To assess efficacy of transplantation of PKX-001 treated islets To assess efficacy of addition of PKX-001 during islet preservation

Procedures:

Prior to transplantation, the patient is screened, qualified, listed for transplant, and signs the informed consent form.

At the time a suitable islet preparation becomes available, the patient will receive allogeneic islet cells transplanted into patients intraportally by percutaneous transhepatic access.

Islet transplant will be performed under the current immunosuppression regimen including: induction (Alemtuzumab/Basiliximab) and long-term immunosuppression (Prograf/Cellcept). The engraftment regimen includes anti-inflammatory medications (Etanercept/Anakinra) and intravenous insulin and heparin. The only additional intervention used in this pilot trial is the addition of the investigational agent, PKX-001 to islet processing.

Follow up:

Participants will undergo a 3-month follow-up period following their initial or subsequent islet transplant.

There are no study-specific follow-up visits required for this study. Study subjects will be followed as per standard of care. For the purpose of evaluating the primary and secondary endpoints, the following measurements collected on study subjects at the time points indicated as per standard of care, will be chart reviewed and recorded up to Day 30 post-transplant:

Clinical Assessment by Transplant Fellow or Staff; Post-Transplant Blood work (as per Standard of Care); Metabolic testing: Ensure (or Arginine); Glucose Records for Self-Monitoring. Incidence of Primary Non-Function (see Glossary for definition); Incidence of Adverse Events or Serious Adverse Events can be reported on any day post transplant; Abdominal Ultrasound with Doppler report (clinically significant findings). The study will remain open to collect all 10 recipients' follow-up data to 3 month post-transplant. Primary and secondary outcome reporting will occur 90 days following the transplant of the last patient to the trial.