CLINICAL TRIALS | XenoTherapeutics | United States

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CLINICAL TRIALS

FDA UPDATE

After years of focused work by some of the leading researchers in the field of xenotransplantation, we have submitted an Investigational New Drug (IND) application (IND# 18914) with the U.S. Food and Drug Administration and were approved to conduct first-in-human clinical trials of our Xeno-Skin xenotransplantation product, designed to provide a safe temporary coverage mechanism for patients with severe and extensive, deep partial and full-thickness burn wounds.

CLICK HERE to learn more about our trial on Clinicaltrials.gov

OUR PUBLICATIONS

Paul W. Holzer, Elizabeth Chang, Joan Wicks, Linda Scobie, Claire Crossan, Rod Monroy, Immunological response in cynomolgus macaques to porcine α-1,3 galactosyltransferase knockout viable skin xenotransplants—A pre-clinical study, Xenotransplantation, https://doi.org/10.1111/xen.12632

Paul Holzer, Jon Adkins, Krysta Moulton, Laurence Zhu, Rod Monroy, Curtis L Cetrulo, Vital, Porcine, Gal-Knockout Skin Transplants Provide Efficacious Temporary Closure of Full-Thickness Wounds: Good Laboratory Practice-Compliant Studies in Nonhuman Primates, Journal of Burn Care & Research, irz124, https://doi.org/10.1093/jbcr/irz124

Paul W. Holzer, Alexandre Lelouch, Krysta Moulton, Laurence Zhu, Zhi Y Ng, Bo Overschmidt, Amon-Ra Gama, Angelo Leto Barone, Ivy Rosales, Rod Monroy, Curtis L Cetrulo, Clinical Impact of Cryopreservation on Split Thickness Skin Grafts in the Porcine Model, Journal of Burn Care & Research, irz145, https://doi.org/10.1093/jbcr/irz145

Paul W. Holzer, David A. Leonard, Kumaran Shanmugarajah, Krysta N. Moulton, Zhi Yang Ng, Curtis L. Cetrulo, David H. Sachs, A Comparative Examination of the Clinical Outcome and Histological Appearance of Cryopreserved and Fresh Split-Thickness Skin Grafts, Journal of Burn Care & Research, Volume 38, Issue 1, January-February 2017, Pages e55–e61, https://doi.org/10.1097/BCR.0000000000000431

REGULATORY PUBLICATIONS

Source Animal, Product, Preclinical Issues Concerning the Use of Xenotransplantation Products in Humans,” located at https://www.fda.gov/media/102126/download.

Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs),” from April 2008 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/content-and-review-chemistry-manufacturing-and-control-cmc-information-human-somatic-cell-therapy)

Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics; Chemistry, Manufacturing, and Controls Documentation” (May 1999, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070551.pdf)

Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, Questions and Answers” (May 2002, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070553.pdf)

Good Clinical Practice: Integrated Addendum to ICH E6(R1) (March 2018), available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e6r2-good-clinical-practice-integrated-addendum-ich-e6r1

Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products (November 2013), available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM376521.pdf

OTAT Learn Webinar Series at: http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm

FDA’s guidance for industry Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products (June 2015), available at https://www.fda.gov/media/106369/download

Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies (2012), available at https://www.fda.gov/media/79394/download

Guidance for Industry: Safety Assessment for IND Safety Reporting (2015), available at https://www.fda.gov/media/94879/download

Target Product Profile — A Strategic Development Process Tool (March 2007), available at https://www.fda.gov/media/72566/download

FDA Expertise Advancing the Understanding of Intentional Genomic Alterations in Animal, available at https://www.fda.gov/news-events/press-announcements/fda-expertise-advancing-understanding-intentional-genomic-alterations-animals?mkt_tok=eyJpIjoiTVRJNE5ETmpNVFl4TWpKaSIsInQiOiJTSTdLTzRUcUFrWHR4cEFMck9XNVVNZG5jNzMxZE4ydTBjT3FIVUlVN2hNdE1SbmJGYzlNOG1Cb3VmdlJpVkljQndXNWxmU2JpQ3cxNU50b1VCM1dQN0pWY29qZm5SZVg1WFd6NWQ2MVNiNllRT3k3XC90R3pcL3lwdDhBYzVRVHVYIn0%3D

OTHER PUBLICATIONS

Albritton A, Leonard DA, Leto Barone A, Keegan J, Mallard C, Sachs DH, Kurtz JM, Cetrulo CL Jr. Lack of cross-sensitization between α-1,3-galactosyltransferase knockout porcine and allogeneic skin grafts permits serial grafting. Transplantation. 2014 Jun 27;97(12):1209-15. doi: 10.1097/TP.0000000000000093.

Bruccoleri RE, Matthew MK, Schulz JT. Methods in obtaining split-thickness skin grafts from skin reduction surgery specimens. Springerplus. 2016 May 25;5(1):690. doi: 10.1186/s40064-016-2330-2. eCollection 2016.

Burd A, Chiu T. Allogenic skin in the treatment of burns. Clin Dermatol. 2005 Jul-Aug;23(4):376-87. Review.

Denner J. Paving the Path toward Porcine Organs for Transplantation. N Engl J Med. 2017 Nov 9;377(19):1891-1893. doi: 10.1056/NEJMcibr1710853.

Deschamps JY, Roux FA, Saï P, Gouin E. History of xenotransplantation. Xenotransplantation. 2005 Mar;12(2):91-109.

Ericsson TA, Takeuchi Y, Templin C, Quinn G, Farhadian SF, Wood JC, Oldmixon BA, Suling KM, Ishii JK, Kitagawa Y, Miyazawa T, Salomon DR, Weiss RA, Patience C. Identification of receptors for pig endogenous retrovirus. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6759-64. Epub 2003 May 9.

Fishman JA. Screening of source animals and clinical monitoring for xenotransplantation. Xenotransplantation. 2007, 349-352.

Fishman JA, Scobie L, Takeuchi Y. Xenotransplantation-associated infectious risk: a WHO consultation. Xenotransplantation. 2012 Mar-Apr;19(2):72-81. doi: 10.1111/j.1399-3089.2012.00693.x.

Godehardt AW, Rodrigues Costa M, Tönjes RR. Review on porcine endogenous retrovirus detection assays--impact on quality and safety of xenotransplants. Xenotransplantation. 2015 Mar-Apr;22(2):95-101. doi: 10.1111/xen.12154. Epub 2015 Jan 31. Review.

Herndon DN. Total Burn Care, Expert Consult - Online. Elsevier Health Sciences; 2012.

Johnson RM, Richard R. Partial-thickness burns: identification and management. Adv Skin Wound Care. 2003 Jul-Aug;16(4):178-87; quiz 188-9. Review.

Kitala D, Kawecki M, Klama-Baryła A, Łabuś W, Kraut M, Glik J, Ryszkiel I, Kawecki MP, Nowak M. Allogeneic vs. Autologous Skin Grafts in the Therapy of Patients with Burn Injuries: A Restrospective, Open-label Clinical Study with Pair Matching. Adv Clin Exp Med. 2016 Sep-Oct;25(5):923-929. doi: 10.17219/acem/61961.

Leonard DA, Mallard C, Albritton A, Torabi R, Mastroianni M, Sachs DH, Kurtz JM, Cetrulo CL Jr. Skin grafts from genetically modified α-1,3-galactosyltransferase knockout miniature swine: A functional equivalent to allografts. Burns. 2017 Dec;43(8):1717-1724. doi: 10.1016/j.burns.2017.04.026. Epub 2017 Jun 8.

Leto Barone AA, Mastroianni M, Farkash EA, Mallard C, Albritton A, Torabi R, Leonard DA, Kurtz JM, Sachs DH, Cetrulo CL Jr. Genetically modified porcine split-thickness skin grafts as an alternative to allograft for provision of temporary wound coverage: preliminary characterization. Burns. 2015 May;41(3):565-74. doi: 10.1016/j.burns.2014.09.003. Epub 2014 Oct 16.

Organ Procurement and Transplantation Network. (n.d.). Retrieved May 01, 2017, from https://optn.transplant.hrsa.gov/

Martin SI, Wilkinson R, Fishman JA. Genomic presence of recombinant porcine endogenous retrovirus in transmitting miniature swine. Virol J. 2006 Nov 2;3:91.

Meije Y, Tönjes RR, Fishman JA. Retroviral restriction factors and infectious risk in xenotransplantation. Am J Transplant. 2010 Jul;10(7):1511-6. doi: 10.1111/j.1600-6143.2010.03146.x.

Morozov VA, Wynyard S, Matsumoto S, Abalovich A, Denner J, Elliott R. No PERV transmission during a clinical trial of pig islet cell transplantation. Virus Res. 2017 Jan 2;227:34-40. doi: 10.1016/j.virusres.2016.08.012. Epub 2016 Sep 24.

Paradis K, Langford G, Long Z, Heneine W, Sandstrom P, Switzer WM, Chapman LE, Lockey C, Onions D, Otto E. Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group. Science. 1999 Aug 20;285(5431):1236-41.

Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nat Med. 1997 Mar;3(3):282-6.

Sachs DH. The lure of transplantation. Clin Transpl. 2008:287-305.

Schaffer A. Cadaver Skin Fills the Gap in Burn Cases. New York Times. https://www.nytimes.com/2006/05/02/health/02skin.html. May 2, 2006.

Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, Gottrup F, Gurtner GC, Longaker MT. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 2009 Nov-Dec;17(6):763-71. doi: 10.1111/j.1524-475X.2009.00543.x.

Sheridan RL, Tompkins RG. Skin substitutes in burns. Burns. 1999 Mar;25(2):97-103. Review.

Shi M, Wang X, Okamoto M, Takao S, Baba M. Inhibition of porcine endogenous retrovirus (PERV) replication by HIV-1 gene expression inhibitors. Antiviral Res. 2009 Aug;83(2):201-4. doi: 10.1016/j.antiviral.2009.04.011. Epub 2009 May 3.

Thorton JF and Gosman AA. Skin Grafts and Skin Substitutes. Baylor University Medical Center. 2004 10(1): 2-78

Weiner J, Yamada K, Ishikawa Y, Moran S, Etter J, Shimizu A, Smith RN, Sachs DH. Prolonged survival of GalT-KO swine skin on baboons. Xenotransplantation. 2010 Mar-Apr;17(2):147-52. doi: 10.1111/j.1399-3089.2010.00576.x.

Wilhelm M, Fishman JA, Pontikis R, Aubertin AM, Wilhelm FX. Susceptibility of recombinant porcine endogenous retrovirus reverse transcriptase to nucleoside and non-nucleoside inhibitors. Cell Mol Life Sci. 2002 Dec;59(12):2184-90.

Wood JC, Quinn G, Suling KM, Oldmixon BA, Van Tine BA, Cina R, Arn S, Huang CA, Scobie L, Onions DE, Sachs DH, Schuurman HJ, Fishman JA, Patience C. Identification of exogenous forms of human-tropic porcine endogenous retrovirus in miniature Swine. J Virol. 2004 Mar;78(5):2494-501.

World Health Organization Burn Fact Sheet. http://www.who.int/en/news-room/fact-sheets/detail/burns. March 6, 2018.

Wynyard S, Nathu D, Garkavenko O, Denner J, Elliott R. Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand. Xenotransplantation. 2014 Jul-Aug;21(4):309-23. doi: 10.1111/xen.12102. Epub 2014 May 7.

Yue S, Zhang Y, Gao Y. A study on the susceptibility of allogeneic human hepatocytes to porcine endogenous retrovirus. Eur Rev Med Pharmacol Sci. 2015 Sep;19(18):3486-91.

Holzer PW, Leonard DA, Shanmugarajah K, Moulton KN, Ng ZY, Cetrulo CL Jr, Sachs DH. A Comparative Examination of the Clinical Outcome and Histological Appearance of Cryopreserved and Fresh Split-Thickness Skin Grafts. J Burn Care Res. 2017 Jan/Feb;38(1):e55-e61. doi: 10.1097/BCR.0000000000000431.

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