DIABECELL®

Life-changing cellular therapy
for Type 1 diabetes.

DIABECELL® is a porcine, insulin-producing cell product for the treatment of Type 1 diabetes. These islet cells are self-regulating and efficiently secrete insulin in the patient’s body.

The treatment involves introducing encapsulated porcine cells into the abdominal cavity of the patient in a simple procedure. LCT’s encapsulation technology means that this procedure does not require the use of immunosuppressant drugs.

Clinical Trials

LCT is conducting clinical trials in Russia to test the safety and efficacy of DIABECELL®. To be kept informed of developments, please click here to sign up. The Ministry of Health has authorised clinical trials in N.Z. and patient enrolment has commenced. The first implant was in October 2009. For information on the NZ trial refer to http://clinicaltrials.gov/ct2/show/NCT00940173?term=porcine+islets&rank=1

Product demand

• Diabetes is the world’s fastest growing chronic disease that affects 246 million people worldwide and the World Health Organisation expects this number to rise to 380 million by 2025
• Type 1 diabetes represents 10-15% of all diabetes cases
• In Australia, diabetes is the sixth leading cause of death
• 890,000 Australians are currently diagnosed but it is thought that the total number of Australians with Type 1 and 2 diabetes and pre-diabetes is around 3.2 million
• In 2007, diabetes cost the US economy $174 billion and it is estimated that one in every 10 health dollars in the US is spent on diabetes
• It is estimated that approximately 4.9 million people (in all age groups) have type 1 diabetes. The European region has the highest estimated number of people with type 1 diabetes (1.27 million), followed by the North American region (1.04 million) and the South East Asian region (0.91 million)
• The World Health Organisation (WHO) estimates that 2.5 to 15% of annual health budgets are spent on diabetes-related illnesses

Product Development

Russia

LCT has a Phase I/IIa clinical trial currently underway in Russia. The trial is monitored by a Boston-based contract research organisation. A total of up to 10 patients will receive DIABECELL® implants of varying dose strength. Some patients will receive multiple doses.

New Zealand

LCT has commenced its Phase II trial at Middlemore Hospital in Auckland. Four patients will receive implants of 10,000 IEQ and another four 15,000 IEQ.

DIABECELL®

• DIABECELL’s safety and efficacy have been demonstrated in preclinical trials
• The long term safety of DIABECELL® has been demonstrated in at least one patient whose implanted cells are still producing insulin after 10 years

Publications

• Elliott RB, Escobar L, Tan PL, Muzina M, Zwain S, Buchanan C.
  Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation. 2007 Mar;14(2):157-61. Read abstract

  Xenotransplantation. 2007 Mar;14(2):157-61
  Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation.
  Elliott RB, Escobar L, Tan PL, Muzina M, Zwain S, Buchanan C.
  Living Cell Technologies, Aukland, New Zealand. relliott@lctglobal.com

  BACKGROUND: The long-term viability and function of transplanted encapsulated neonatal porcine islets was examined in a diabetic patient.

  METHODS AND RESULTS: A 41-yr-old Caucasian male with type 1 diabetes for 18 yr was given an intraperitoneal transplant of alginate-encapsulated porcine islets at the dose of 15,000 islet equivalents (IEQs)/kg bodyweight (total dose 1,305,000 IEQs) via laparoscopy. By 12 weeks following the transplant, his insulin dose was significantly reduced by 30% (P = 0.0001 by multiple regression tests) from 53 units daily prior to transplant. The insulin dose returned to the pre-transplant level at week 49. Improvement in glycaemic control continued as reflected by total glycated haemoglobin of 7.8% at 14 months from a pre-transplant level of 9.3%. Urinary porcine C-peptide peaked at 4 months (9.5 ng/ml) and remained detectable for 11 months (0.6 ng/ml). The patient was followed as part of a long-term microbiologic monitoring programme which subsequently showed no evidence of porcine viral or retroviral infection. At laparoscopy 9.5 yr after transplantation, abundant nodules were seen throughout the peritoneum. Biopsies of the nodules showed opacified capsules containing cell clusters that stained as live cells under fluorescence microscopy. Immunohistology noted sparse insulin and moderate glucagon staining cells. The retrieved capsules produced a small amount of insulin when placed in high glucose concentrations in vitro. An oral glucose tolerance test induced a small rise in serum of immuno-reactive insulin, identified as porcine by reversed phase high pressure liquid chromatography.

  CONCLUSION: This form of xenotransplantation treatment has the potential for sustained benefit in human type 1 diabetics.

• Elliott RB, Escobar L, Tan PL, Garkavenko O, Calafiore R, Basta P, Vasconcellos AV, Emerich DF, Thanos C, Bambra C.
  Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant Proc. 2005 Oct;37(8):3505-8. Read abstract

  Transplant Proc. 2005 Oct;37(8):3505-8.
  Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates.
  Elliott RB, Escobar L, Tan PL, Garkavenko O, Calafiore R, Basta P, Vasconcellos AV, Emerich DF, Thanos C, Bambra C.Living Cell Technologies New Zealand, Ltd., PO Box 23-566 Hunters Corner, Papatoetoe, Auckland, New Zealand. relliott@lctglobal.com

  BACKGROUND: A nonhuman primate model of diabetes is valuable for assessing porcine pancreatic islet transplants that might have clinical benefits in humans.

  METHODS: Neonatal porcine islets, microencapsulated in alginate-polyornithine-alginate, were injected intraperitoneally (10,000 IEQs/kg islets) into eight adult male cynomolgus monkeys rendered diabetic with streptozotocin. Eight diabetic controls were given an equivalent dose of empty placebo capsules. All subjects received a repeat transplant 3 months after the first. RESULTS: The transplant was well tolerated and no adverse or hypoglycemic events occurred. There were two deaths from nontransplant treatment or diabetic complications unrelated to the transplants. After transplantation, the average insulin dose was reduced in the islet-treated group and increased in the control group. At 12 weeks after the first transplant there was a mean 36% (95% CI: 6% to 65%, P = .02) drop in daily insulin dose compared with the control group. After 24 weeks the difference increased to a mean of 43% (95% CI: 12% to 75%, P = .01) without significant differences in blood glucose values between the two groups. Individual responses after islet transplant varied and one monkey was weaned off insulin by 36 weeks. At terminal autopsy, organs appeared normal and there was no visible peritoneal reaction. No animal had polymerase chain reaction (PCR)-amplified signals of porcine endogenous retrovirus or exogenous virus infections in blood or tissues.

  CONCLUSION: Repeated intraperitoneal transplantation of microencapsulated neonatal porcine islets is a safe procedure in diabetic primates. It was shown to result in a significant reduction in insulin dose requirement in the majority of animals studied, whereas insulin requirement increased in controls.
• Valdés-González RA, Dorantes LM, Garibay GN, Bracho-Blanchet E, Mendez AJ, Dávila-Pérez R, Elliott RB, Terán L, White DJ.
  Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study. Eur J Endocrinol. 2005 Sep;153(3):419-27. Read abstract

  Eur J Endocrinol. 2005 Sep;153(3):419-27
  Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study.
  Valdés-González RA, Dorantes LM, Garibay GN, Bracho-Blanchet E, Mendez AJ, Dávila-Pérez R, Elliott RB, Terán L, White DJ. Facultad de Medicina, Universidad Nacional Autónoma de México, D.F. Mexico. rvaldes@xenomexico.org

  OBJECTIVE: Porcine islets of Langerhans for xenotransplantation into humans have been proposed as a solution to the shortage of human donors. Rejection is one of the main constraints. This study presents the results of a clinical trial using a novel method for transplanting and immunoprotecting porcine islets in type 1 diabetic patients. DESIGN: A 4-year follow up of a clinical trial involving 12 patients, with no immunosuppressive drugs at any point. Eleven age matched untransplanted diabetics served as controls.

  METHODS: We have developed a procedure for protecting neonatal porcine islets by combining them with Sertoli cells and placing them in a novel subcutaneous autologous collagen-covered device. RESULTS: In the patients in the treatment group, no complications arose and no porcine endogenous retrovirus infection was detected. Half of the patients showed a significant reduction in insulin requirements compared with both their pre transplant levels and controls, and this reduction was maintained for up to 4 years. Two patients became insulin-independent for several months. Porcine insulin was detected in three patients' sera following glucose stimulation up to 4 years post transplant. Three years post transplant, one of four devices was removed from four patients, and the presence of insulin-positive cells in the transplant was demonstrated by immunohistology in all 4 patients.

  CONCLUSIONS: Long-term cell survival with concurrent positive effects on metabolic control are possible by this technique.

• Garkavenko O, Elliott RB, Croxson MC.
  Identification of pig circovirus type 2 in New Zealand pigs. Transplant Proc. 2005 Jan-Feb;37(1):506-9. Read abstract

  Transplant Proc. 2005 Jan-Feb;37(1):506-9.
  Identification of pig circovirus type 2 in New Zealand pigs.
  Garkavenko O, Elliott RB, Croxson MC.
  Living Cell Technologies Ltd, New Zealand. olga@diatranz.co.nz

  Interest in porcine circovirus has been stimulated by the recent emergence of postweaning multisystemic wasting syndrome (PMWS) in pigs and the potential use of pig organs for xenotransplantation in humans. Porcine circovirus type 1 (PCV1) is considered to be widespread in pigs but nonpathogenic. Circovirus type 2 (PCV2) is a similar virus but has been differentiated only recently as a separate type. High tissue concentrations of PCV2 are associated with lesions in PMWS cases, but the etiological role of this agent in the disease remains unclear. The presence of PCV1 in New Zealand pigs has been previously reported based on serological data. PMWS has been recently recorded in New Zealand pigs. The epidemiology of PCV2 in New Zealand pigs has not been examined. The purpose of the study was to look for evidence of circoviruses in New Zealand pig herds. Pig circovirus DNA was sought in various tissues using the polymerase chain reaction. Circovirus type 2 was found in New Zealand pig herds, without any evidence that PMWS has ever occurred in these herds. Newborn piglets were shown to have infection, suggesting vertical transmission of the virus.

• Elliott RB, Escobar L, Calafiore R, Basta G, Garkavenko O, Vasconcellos A, Bambra C.
  Transplantation of micro- and macroencapsulated piglet islets into mice and monkeys. Transplant Proc. 2005 Jan-Feb;37(1):466-9. Read abstract

  Transplant Proc. 2005 Jan-Feb;37(1):466-9.
  Transplantation of micro- and macroencapsulated piglet islets into mice and monkeys.
  Elliott RB, Escobar L, Calafiore R, Basta G, Garkavenko O, Vasconcellos A, Bambra C.
  Living Cell Technologies, Auckland, New Zealand. bobe@diatranz.co.nz

  Neonatal porcine islets within alginate microcapsules transplanted intraperitoneally (IP) or within semi-permeable macrocapsules (TheraCyte) and transplanted subcutaneously (SC) survive and reverse diabetes for up to 16 weeks in diabetic autoimmune nonobese diabetic (NOD) mice. The islets in microcapsules transplanted IP into nondiabetic cynomolgus monkeys survived for 8 weeks. Similar results were shown with islets transplanted in TheraCytes. Neither species showed adverse effects or evidence of infection with porcine endogenous retroviruses or other endemic pig viruses. Proof of principle is illustrated for successful xenotransplantation in humans.

• Garkavenko O, Croxson MC, Irgang M, Karlas A, Denner J, Elliott RB.
  Monitoring for presence of potentially xenotic viruses in recipients of pig islet xenotransplantation. J Clin Microbiol. 2004 Nov;42(11):5353-6. Read abstract

  J Clin Microbiol. 2004 Nov;42(11):5353-6.
  Monitoring for presence of potentially xenotic viruses in recipients of pig islet xenotransplantation.
  Garkavenko O, Croxson MC, Irgang M, Karlas A, Denner J, Elliott RB.
  Diatranz NZ Ltd., P.O. Box 23566, Papatoetoe, Auckland, New Zealand. ovlad@xtra.co.nz

  This study represents a long-term follow-up of human patients receiving pig islet xenotransplantation. Eighteen patients had been monitored for up to 9 years for potentially xenotic pig viruses: pig endogenous retrovirus, pig cytomegalovirus, pig lymphotropic herpesvirus, and pig circovirus type 2. No evidence of viral infection was found.

• Garkavenko O, Muzina M, Muzina Z, Powels K, Elliott RB, Croxson MC.
  Monitoring for potentially xenozoonotic viruses in New Zealand pigs. J Med Virol. 2004 Feb;72(2):338-44. Read abstract

  J Med Virol. 2004 Feb;72(2):338-44.
  Monitoring for potentially xenozoonotic viruses in New Zealand pigs
  Garkavenko O, Muzina M, Muzina Z, Powels K, Elliott RB, Croxson MC.
  Virology Laboratory, Diatranz Ltd., Auckland, New Zealand. olga@diatranz.co.nz

  Shortage of human donor organs for transplantation has prompted evaluation of animals as an alternative donor source. Pigs are the most acceptable candidate animals but issues of xenozoonozes remain. Despite careful monitoring of high-health-status (HHS) pigs, there is still a risk that their tissues may carry infectious agents. Furthermore, pathogens which are significant in xenotransplantation are not necessarily those of veterinary importance. The detection of these potentially transmissible infectious agents may require the development and application of new surveillance technologies. We present data on monitoring for five potentially xenotic viruses in New Zealand pig herds, namely pig cytomegalovirus (PCMV), pig lymphotropic herpesvirus (PLHV), encephalomyocarditis virus (EMCV), pigcircovirus (PCV), and hepatitis E virus (HEV). These five viruses are either potentially oncogenic, establish persistent infection, or are known to be zoonotic. This study has expanded significantly the information on porcine viruses in New Zealand. Using this information, it is now possible to complete protocols for monitoring pig herds and tissues prior to their use in xenotransplantation. The study resulted in selection of a possible source herd for swine-to-human islet transplantation.

• Elliott RB, Garkavenko O, Escobar L, Skinner S.
  Concerns expressed about the virological risks of xenotransplantation. Xenotransplantation. 2002 Nov;9(6):422-4. No abstract available.
  
  
• Elliott RB, Escobar L, Garkavenko O, Croxson MC, Schroeder BA, McGregor M, Ferguson G, Beckman N, Ferguson S.
  No evidence of infection with porcine endogenous retrovirus in recipients of encapsulated porcine islet xenografts. Cell Transplant. 2000 Nov-Dec;9(6):895-901. Read abstract

  Cell Transplant. 2000 Nov-Dec;9(6):895-901
  No evidence of infection with porcine endogenous retrovirus in recipients of encapsulated porcine islet xenografts.
  Elliott RB, Escobar L, Garkavenko O, Croxson MC, Schroeder BA, McGregor M, Ferguson G, Beckman N, Ferguson S.
  Diatranz Ltd, Auckland, New Zealand. elliott@diatranz.co.nz

  Transplantation of pig tissues into humans has the potential for cotransferring pig infections. Knowledge of the epidemiology of pig infections transmissible to humans allows the development of risk limitation strategies at the source herd level, but potentially infectious pig endogenous retrovirus (PERV) is ubiquitous in all domestic pigs and therefore is not avoidable. Using a specific and sensitive RT-PCR and nested PCR for PERV nucleic acids with primers, the screening of pigs from New Zealand herds for the presence and expression of the PERV was conducted. The presence of PERV proviral DNA (pol and env region) and viral RNA was demonstrated in all tested pig tissues including pancreas, liver, spleen, brain, heart, and PBMC. Using the same assays it was established that different tissues (liver, spleen, and heart) of nude and nonobese diabetic (NOD) mice previously transplanted with nonencapsulated pig islets were PERV DNA and RNA negative. Alginate polylysine capsules prepared with encapsulated pig islets were tested for possible leakage of viral particles or viral nucleic acids. RNA was extracted from the supernatant of viable encapsulated pig islet cells grown in culture for 2 months. No evidence of PERV RNA or of cellular nucleic acids could be found. Two adult type I diabetic subjects were transplanted with 1 x 10(6) neonatal pig islets encased in alginate capsules into the peritoneal cavity. One patient was immunosuppressed. Both showed evidence of graft function (up to 34% reduction in insulin dose, corresponding increase in serum pig C-peptide) for up to 2 years. DNA and RNA were extracted from PBMC and blood plasma of both patients at 19 months posttransplant. No evidence of PERV proviral DNA or RNA could be detected. Piglet islets contain PERV DNA and RNA, but this does not traverse the capsules used or produce any evidence of infection in nude and nonobese diabetic (NOD) mice or humans.