MedKoo product information:

Ingenol Mebutate

According to a news published by prnewswire.com  in Feb 2010,  LEO Pharma today announced that in a Phase III study, PEP005 (ingenol mebutate) Gel, the company's lead candidate for the topical treatment of actinic (solar) keratosis (AK) or pre-cancerous lesions, met its primary clinical endpoint of complete clearance of AK lesions in non-head locations.  Findings from the REGION Ib study in body AK support results from the earlier REGION-I trial, a study evaluating PEP005 for the treatment of AK on the head reported in December 2009.

Current developer:   Peplin;  LEO Pharma.

 1: Siller G, Rosen R, Freeman M, Welburn P, Katsamas J, Ogbourne SM. PEP005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: results of a randomized phase IIa trial. Australas J Dermatol. 2010 May;51(2):99-105. PubMed PMID: 20546215.

2: Lee WY, Hampson P, Coulthard L, Ali F, Salmon M, Lord JM, Scheel-Toellner D. Novel Antileukemic Compound Ingenol 3-Angelate Inhibits T Cell Apoptosis by Activating Protein Kinase C{theta}. J Biol Chem. 2010 Jul 30;285(31):23889-98. Epub 2010 May 14. PubMed PMID: 20472553.

3: Hampson P, Wang K, Milverton L, Ersvaer E, Bruserud O, Lord JM. Kinetics of ERK1/2 activation determine sensitivity of acute myeloid leukaemia cells to the induction of apoptosis by the novel small molecule ingenol 3-angelate (PEP005). Apoptosis. 2010 Aug;15(8):946-55. PubMed PMID: 20467815.

4: Li L, Shukla S, Lee A, Garfield SH, Maloney DJ, Ambudkar SV, Yuspa SH. The skin cancer chemotherapeutic agent ingenol-3-angelate (PEP005) is a substrate for the epidermal multidrug transporter (ABCB1) and targets tumor vasculature. Cancer Res. 2010 Jun 1;70(11):4509-19. Epub 2010 May 11. PubMed PMID: 20460505; PubMed Central PMCID: PMC2880198.

5: Reikvam H, Hatfield KJ, Oyan AM, Kalland KH, Kittang AO, Bruserud O. Primary human acute myelogenous leukemia cells release matrix metalloproteases and their inhibitors: release profile and pharmacological modulation. Eur J Haematol. 2010 Mar;84(3):239-51. Epub 2009 Nov 17. PubMed PMID: 19922462.

6: Anderson L, Schmieder GJ, Werschler WP, Tschen EH, Ling MR, Stough DB, Katsamas J. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol. 2009 Jun;60(6):934-43. PubMed PMID: 19467365.

7: Le TT, Gardner J, Hoang-Le D, Schmidt CW, MacDonald KP, Lambley E, Schroder WA, Ogbourne SM, Suhrbier A. Immunostimulatory cancer chemotherapy using local ingenol-3-angelate and synergy with immunotherapies. Vaccine. 2009 May 18;27(23):3053-62. Epub 2009 Apr 3. PubMed PMID: 19428919.

8: Ghoul A, Serova M, Astorgues-Xerri L, Bieche I, Bousquet G, Varna M, Vidaud M, Phillips E, Weill S, Benhadji KA, Lokiec F, Cvitkovic E, Faivre S, Raymond E. Epithelial-to-mesenchymal transition and resistance to ingenol 3-angelate, a novel protein kinase C modulator, in colon cancer cells. Cancer Res. 2009 May 15;69(10):4260-9. Epub 2009 May 5. PubMed PMID: 19417139.

9: Olsnes AM, Ersvaer E, Ryningen A, Paulsen K, Hampson P, Lord JM, Gjertsen BT, Kristoffersen EK, Bruserud Ø. The protein kinase C agonist PEP005 increases NF-kappaB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells. Br J Haematol. 2009 Jun;145(6):761-74. Epub 2009 Apr 20. PubMed PMID: 19388934.

10: Siller G, Gebauer K, Welburn P, Katsamas J, Ogbourne SM. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study. Australas J Dermatol. 2009 Feb;50(1):16-22. PubMed PMID: 19178487.

11: Benhadji KA, Serova M, Ghoul A, Cvitkovic E, Le Tourneau C, Ogbourne SM, Lokiec F, Calvo F, Hammel P, Faivre S, Raymond E. Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells. Br J Cancer. 2008 Dec 2;99(11):1808-15. PubMed PMID: 19034280; PubMed Central PMCID: PMC2600681.

12: Serova M, Ghoul A, Benhadji KA, Faivre S, Le Tourneau C, Cvitkovic E, Lokiec F, Lord J, Ogbourne SM, Calvo F, Raymond E. Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. Mol Cancer Ther. 2008 Apr;7(4):915-22. PubMed PMID: 18413805.

13: Hampson P, Kavanagh D, Smith E, Wang K, Lord JM, Ed Rainger G. The anti-tumor agent, ingenol-3-angelate (PEP005), promotes the recruitment of cytotoxic neutrophils by activation of vascular endothelial cells in a PKC-delta dependent manner. Cancer Immunol Immunother. 2008 Aug;57(8):1241-51. Epub 2008 Feb 12. PubMed PMID: 18265980.

14: Ersvaer E, Hampson P, Wendelbo Ø, Lord JM, Gjertsen BT, Bruserud Ø. Circulating T cells in patients with untreated acute myelogenous leukemia are heterogeneous and can be activated through the CD3/TCR complex. Hematology. 2007 Jun;12(3):199-207. PubMed PMID: 17558695.

15: Ogbourne SM, Hampson P, Lord JM, Parsons P, De Witte PA, Suhrbier A. Proceedings of the First International Conference on PEP005. Anticancer Drugs. 2007 Mar;18(3):357-62. PubMed PMID: 17264770.

16: Ersvaer E, Hampson P, Hatfield K, Ulvestad E, Wendelbo Ø, Lord JM, Gjertsen BT, Bruserud Ø. T cells remaining after intensive chemotherapy for acute myelogenous leukemia show a broad cytokine release profile including high levels of interferon-gamma that can be further increased by a novel protein kinase C agonist PEP005. Cancer Immunol Immunother. 2007 Jun;56(6):913-25. Epub 2006 Nov 8. PubMed PMID: 17115221.

17: Challacombe JM, Suhrbier A, Parsons PG, Jones B, Hampson P, Kavanagh D, Rainger GE, Morris M, Lord JM, Le TT, Hoang-Le D, Ogbourne SM. Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J Immunol. 2006 Dec 1;177(11):8123-32. PubMed PMID: 17114487.

18: Cozzi SJ, Parsons PG, Ogbourne SM, Pedley J, Boyle GM. Induction of senescence in diterpene ester-treated melanoma cells via protein kinase C-dependent hyperactivation of the mitogen-activated protein kinase pathway. Cancer Res. 2006 Oct 15;66(20):10083-91. PubMed PMID: 17047072.

19: Hampson P, Chahal H, Khanim F, Hayden R, Mulder A, Assi LK, Bunce CM, Lord JM. PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. Blood. 2005 Aug 15;106(4):1362-8. Epub 2005 Apr 21. PubMed PMID: 15845901.

20: Gillespie SK, Zhang XD, Hersey P. Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells. Mol Cancer Ther. 2004 Dec;3(12):1651-8. PubMed PMID: 15634659.

21: Ogbourne SM, Suhrbier A, Jones B, Cozzi SJ, Boyle GM, Morris M, McAlpine D, Johns J, Scott TM, Sutherland KP, Gardner JM, Le TT, Lenarczyk A, Aylward JH, Parsons PG. Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. 2004 Apr 15;64(8):2833-9. PubMed PMID: 15087400.