2013 - IXA 2013 Congress


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IXA Symposium 1: Islet Xenotransplantation: Are we ready for Clinical Islet Xeno Transplantation?

27.1 - Regulatory issues and outcomes of Phase 1 and 2 trials of encapsulted porcine islets for Type 1 diabetes

Presenter: Robert, Elliott, Minneapolis, New Zealand
Authors:

DIABECELL is a microencapsulated neonatal porcine islet preparation prepared under GMP. The source pig herd was qualified following US FDA guidelines. DIABECELL was used in New Zealand after a protracted regulatory process that required two public consultations and approval under a specific section of the New Zealand Medicines Act by the Minister of Health after receiving a recommendation from Medsafe, the NZ regulatory authority. Medsafe consulted the Gene Technology Advisory Committee of the Health Research Council and international referees. Ethical approval was received from the NZ regional ethics committee. The first clinical trial was an open label, safety and dose finding Phase I/IIa study. Four groups of escalating single intraperitoneal doses of 5,000, 10,000, 15,000 or 20,000 IEQ/kg were given IP to Type 1 diabetics with frequent unaware hypoglycaemia despite intensified insulin therapy under specialist supervision. After 1 year, a statistically significant decrease in unaware hypoglycemia scores is evident in the 10,000 IEQ/kg group. However, the 5,000, 10,000, 20,000 IEQ/kg dose also showed lower HYPO scores. The average daily insulin dose decreased in the 10,000 IEQ/kg group. 4 of 14 subjects developed HbA1c of <7% compared to none at baseline. Little adverse effects were noted. Cognisant of the earlier NZ approval, a second study was approved by the Minister of Health, Buenos Aires province and the Bioethical Committee of the Eva Peron Hospital. Two doses of 5,000/kg or 10,000/kg were given to each of two groups of four patients in a similar fashion to the first trial after a two-three month diabetes control optimisation period. Overall unaware hypoglycaemic events were reduced by 57%. All patients (4/4) in the higher dose group reduced UHE by >40% without an increase in HbA1c and 3 of 4 patients in the lower dose group reduced UHE by >30% without an increase in HbA1c. HbA1c fell 1.5-2% in the group receiving the bigger dose. The average daily insulin dose was reduced in 7/8 patients. Hence, the Transplant Estimated Function score was positive in both treatment groups indicating a positive impact of the transplant. Some transient abdominal pain and distension, associated with a rise in C-reactive protein blood levels was seen after the first transplant, but less after the second. No other adverse symptoms were seen. Encapsulated islets recovered at the time of the second implant showed viable islets containing beta cells in intact capsules. Islet xenotransplantation under the conditions used appears to be a safe procedure. It regularly produced considerable reduction in unaware hypoglycaemic events with improvement of hyperglycemia and HbA1c. HbA1c of less than 7% was achieved long term in 5/8 of the subjects with unstable diabetes in the second trial. These results provide invaluable safety and efficacy data as the basis for further improvements in the product and its method of administration.


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