Tecemotide

Tecemotide (INN; emepepimut-S (USAN); formerly known as BLP25 or EMD 531444) is a synthetic lipopeptide that is used as antigen in an investigational therapeutic cancer vaccine (formerly known as Stimuvax, L-BLP25, BLP25 liposomal vaccine or BLP25 liposome vaccine). The investigational therapeutic cancer vaccine is designed to induce a cellular immune response to cancer cells that express MUC1, a glycoprotein antigen that is widely over-expressed on common cancers such as lung cancer, breast cancer, prostate cancer and colorectal cancer. The cellular immune response may lead then to a rejection of tumor tissue expressing the MUC1 antigen.[1]

Collaboration

Tecemotide was developed – until Clinical trial phase II – by the Canadian biotech company Biomira Inc., which changed in 2007 the company name to Oncothyreon Inc.[2] Oncothyreon is now located in Seattle, Washington, USA.

In 2001, Merck KGaA, Darmstadt, Germany, entered into a collaboration and supply agreement with Oncothyreon. In 2007, Merck KGaA acquired the exclusive worldwide marketing rights from Oncothyreon and Merck KGaA is since then entirely responsible for the further clinical development of Tecemotide.[3] In 2008, Merck KGaA acquired the manufacturing rights for Tecemotide from Oncothyreon.[4] In 2011, Ono Pharmaceutical Co., Ltd., Japan, acquired a co-development and co-marketing license for Tecemotide in Japan and Merck KGaA received an upfront payment of 5 million Euros.[5]

Structure

Structure of the cancer vaccine. The antigen tecemotide (orange) and the adjuvant MPL (dark blue) are anchored in the membrane of the liposome. The liposome is formed by the lipids (light blue).[6]

The antigen: Tecemotide

  • International Nonproprietary Name (INN): Tecemotide
  • United States Adopted Name (USAN): Emepepimut-S
BLP25 (Biomira lipopeptide 25) or EMD 531444
Tecemotide is the antigen of the cancer vaccine
human mucin-1 (carcinoma-associated mucin, episialin, CD227)-(107-131)-peptide (sequence 40 times repeated) fusion protein with 6-N-hexadecanoyl-L-lysylglycine
C124H203N33O38
221214-84-2
STAPPAHGVTSAPDTRPAPGSTAPPKG
  • aa 1-25: derived from the mucin 1 (MUC1) sequence
  • aa 26: the modified amino acid K is palmityl-lysin (N6-(1-oxohexadecyl)-L-lysyin)[7]

The adjuvant: MPL

3-O-Deacyl-4’-Monophosphoryl lipid A (MPL) is the adjuvant in the cancer vaccine.[8] MPL is a derivative of the lipid A molecule found in the membrane of Gram-negative bacteria. MPL is also used as adjuvant in other vaccines, e.g. Cervarix which is a vaccine against certain types of cancer-causing human papillomavirus (HPV).

Function:

The carrier: Lipids

Lipids:

Function:

The cancer vaccine: A liposomal formulation

The antigen tecemotide is anchored — together with the adjuvant MPL — in the membrane of the liposome. This liposomal formulation is the investigational therapeutic cancer vaccine (formerly known as Stimuvax, L-BLP25, BLP25 liposomal vaccine or BLP25 liposome vaccine). The cancer vaccine is a lyophilized powder, which is formulated to contain 300 μg of tecemotide and 150 μg of MPL per vial.[10]

Clinical trials

Overview and results of all trials

Tecemotide clinical trials (as of September 2, 2014)[11] sorted by (Estimated) Primary Completion Date:[12]

Overview of completed trials

Overview of completed tecemotide trials (as of September 2, 2014)[25] where results have been published, sorted by Primary Completion Date:[26]

ID Phase Indication Start Primary
Completion
Date 		Summary of the results[27]
EMR 63325-005 2 NSCLC August 2000 March 2006 Subgroup analysis favorable
START, EMR 63325-001 3 NSCLC January 2007 August 2012 Primary endpoint not met. Subgroup analysis favorable
EMR 63325-009 (Japan study) 1, 2 NSCLC December 2008 May 2014 Primary endpoint and secondary endpoints not met. Subgroup analysis not favorable

Merck KGaA discontinues the development of tecemotide in NSCLC (Non-small cell lung cancer)

On August 18, 2014, Oncothyreon[28] and finally on September 12, 2014, also Merck KGaA informed that a randomized Phase 1/2 study, EMR 63325-009, of tecemotide compared to placebo in Japanese patients with Stage III non-small cell lung cancer did not meet its primary endpoint of an improvement in overall survival, and no treatment effect was seen in any of the secondary endpoints (progression free survival, time to progression or time to failure). Merck made the recommendation to stop the investigational treatment of patients in the EMR 63325-009 study in Japan.

Furthermore, Merck KGaA announced its decision to discontinue the Phase III START2 and INSPIRE studies, and all other Merck-sponsored clinical trials with tecemotide in NSCLC worldwide. Merck will continue to supply tecemotide for ongoing investigator-sponsored trials in other indications in accordance with their agreements with the sponsors of these studies.[29]

It remains unclear from Merck’s press release what happens with:

Drug development risks

Risks that could affect the further development of tecemotide published in the annual reports of Oncothyreon (grantor of the license) and Merck KGaA (license holder; responsible for clinical development, marketing and manufacturing):

Risks related to efficacy

As published so far, primary end points have not been met in the clinical studies and tecemotide has shown only treatment effects in statistical analyses of certain subgroups.[30]

Risks related to patent situation

Oncothyreon’s patent protection for tecemotide in the U.S. will expire in 2018.[31]

Risks related to human resources

Merck KGaA is reporting problems with recruiting and retaining qualified employees: "Sourcing, recruiting and retaining specialists and talent at Merck are among the company’s top priorities. Nevertheless, employee-related risks that affect business activities are likely, even though their impact is difficult to assess. Merck rates this as a medium risk."[32]

Merck KGaA is further reporting with respect to its pharma division Merck Serono: "Over 80 % of the Merck Serono senior management positions replaced since 2011 [until Sept. 2014]."[33]

Risks related to novel technologies

Tecemotide is based on novel technologies, which may raise new regulatory issues that could delay or make regulatory approval more difficult. Additionally, to date, the FDA has approved for commercial sale in the United States only one active vaccine designed to stimulate an immune response against cancer. Consequently, there is limited precedent for the successful development or commercialization of products based on these technologies in this area.[34]

Risks related to manufacture

Merck KGaA currently relies on third-party manufacturers to supply the product candidate: On Baxter International Inc. (Baxter), for the manufacture of tecemotide, and on GlaxoSmithKline plc (GSK) for the manufacture of the adjuvant in tecemotide called monophosphoryl lipid A (MPL). If tecemotide is not approved until 2015, GSK may terminate its obligation to supply the adjuvant MPL. In this case, Oncothyreon would retain the necessary licenses from GSK required to have the adjuvant MPL manufactured, but the transfer of the process to a third party would delay the development and commercialization of tecemotide.[35]

GSK is developing the MAGE A3 vaccine in Phase 3, a direct competitor to tecemotide (see section below).

Risks related to competition

Competition in NSCLC: There are currently two products approved as maintenance therapy following treatment of inoperable locoregional Stage III NSCLC with induction chemotherapy, Tarceva (erlotinib), a targeted small molecule from Genentech, Inc., a member of the Roche Group, and Alimta (pemetrexed), a chemotherapeutic from Eli Lilly and Company. Tecemotide has not been tested in combination with or in comparison to these products. It is possible that other existing or new agents will be approved for this indication. In addition, there are at least two vaccines in development for the treatment of NSCLC, including GSK’s MAGE A3 vaccine in Phase 3 and Transgene’s TG-4010 in Phase 2/3. TG-4010 also targets MUC1, although using technology different from tecemotide.[36]

Drug development cost

The cost spent for the tecemotide development – beginning in the late 1990s – have not been published in detail by the companies Biomira/Oncothyreon, Merck KGaA and Ono Pharmaceutical. Additionally, the estimation of full cost of bringing a new drug to market – from discovery through clinical trials to approval – is complex and controversial.

However, a cautious estimate of the tecmotide development cost spent until 2014 ranges from 300 to 500 million Euros (390 to 650 million US$; for more information see Drug development).

History

Date Event
May 1998 Biomira files a BLP25 (tecemotide) patent[37]
May 2001 Biomira licenses BLP25 (tecemotide) to Merck KGaA
Aug 2001 Biomira publishes results of a Phase I study of the BLP25 (tecemotide)[38]
Mar 2006 Results of the Phase IIb Study (EMR 63325-005): Subgroup analysis favorable
Aug 2007 Merck KGaA acquires worldwide marketing rights for tecemotide from Oncothyreon and will be entirely responsible for the further clinical development of tecemotide
Sep 2007 Biomira changes company name to Oncothyreon
Dec 2008 Merck KGaA acquires manufacturing rights for tecemotide from Oncothyreon
Dec 2009 INSPIRE study (EMR63325-012) started. Estimated primary completion date is May 2020
Oct 2011 Ono Pharmaceutical acquires a co-development and co-marketing license for tecemotide in Japan
Dec 2012 Results of the START study (EMR 63325-001): Primary endpoint not met. Subgroup analysis favorable
Mar 2014 START2 study (EMR 63325-021) started. Estimated primary completion date is July 2018
Aug 2014 Results of the Japan study (EMR 63325-009): Primary endpoint and secondary endpoints not met. Subgroup analysis not favorable[39]
Sep 2014 Merck KGaA terminates the NSCLC development

References

  1. ↑ BLP25 liposome vaccine (Tecemotide) long-term safety results from Phase 2b study of patients with stage IIIB and IV non-small cell lung cancer (NSCLC) treated for 2 years or more; World Conference on Lung Cancer, August 2009
  2. ↑ Biomira announces plan to change name to Oncothyreon
  3. ↑ Aug 8, 2007, Biomira and Merck KGaA sign amended and restated collaboration and supply agreements related to Stimuvax
  4. ↑ Dec 18, 2008, Merck KGaA acquires manufacturing rights for Stimuvax from Oncothyreon
  5. ↑ Merck KGaA press release from October 4, 2011
  6. ↑ BLP25 liposome vaccine (Tecemotide) long-term safety results from Phase 2b study of patients with stage IIIB and IV non-small cell lung cancer (NSCLC) treated for 2 years or more; World Conference on Lung Cancer, August 2009
  7. ↑ WHO Drug Information, Vol. 26, No. 4, 2012; Proposed INN: List 108
  8. ↑ BLP25 liposome vaccine (Tecemotide) long-term safety results from Phase 2b study of patients with stage IIIB and IV non-small cell lung cancer (NSCLC) treated for 2 years or more; World Conference on Lung Cancer, August 2009
  9. ↑ BLP25 liposome vaccine (Tecemotide) long-term safety results from Phase 2b study of patients with stage IIIB and IV non-small cell lung cancer (NSCLC) treated for 2 years or more; World Conference on Lung Cancer, August 2009
  10. ↑ BLP25 liposome vaccine (Tecemotide) long-term safety results from Phase 2b study of patients with stage IIIB and IV non-small cell lung cancer (NSCLC) treated for 2 years or more; World Conference on Lung Cancer, August 2009
  11. ↑ ClinicalTrials.gov
  12. ↑ The Primary Completion Date is defined as the date when the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome.
  13. ↑ Butts, C. (2007) Stimuvax (L-BLP25): A Peptide Vaccine Strategy in Non-Small Cell Lung Cancer: M17-03. Journal of Thoracic Oncology 2, Supplement 4, S199–201. doi:10.1097/01.JTO.0000282977.65747.30
  14. ↑ Butts, C., Maksymiuk, A., Goss, G., Soulières, D., Marshall, E., Cormier, Y., Ellis, P.M., Price, A., Sawhney, R., Beier, F., Falk, M., Murray, N. (2011) Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine (L-BLP25): phase IIB randomized, multicenter, open-label trial. Journal of Cancer Research and Clinical Oncology 137, 1337–1342. doi:10.1007/s00432-011-1003-3
  15. ↑ Merck KGaA to test Stimuvax in breast cancer trial (FierceVaccines)
  16. ↑ UPDATE 2-Merck to test Stimuvax cancer drug in Phase III (Thomson Reuters)
  17. ↑ Merck KGaA press release from June 17, 2010
  18. ↑ Experimental Cancer Treatment L-BLP25 (Stimuvax®) Did Not Meet Primary Endpoint of Improvement in Overall Survival in Pivotal Phase III Trial in Patients with Non-Small Cell Lung Cancer (Onco'Zine - The International Cancer Network)
  19. ↑ Butts, C., Socinski, M.A., Mitchell, P.L., Thatcher, N., Havel, L., Krzakowski, M., Nawrocki, S., Ciuleanu, T.-E., Bosquée, L., Trigo, J.M., Spira, A., Tremblay, L., Nyman, J., Ramlau, R., Wickart-Johansson, G., Ellis, P., Gladkov, O., Pereira, J.R., Eberhardt, W.E.E., Helwig, C., Schröder, A., Shepherd, F.A. (2014) Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. The Lancet Oncology 15, 59–68. doi:10.1016/S1470-2045(13)70510-2
  20. ↑ Merck Discontinues Clinical Development Program of Tecemotide as a Monotherapy in Stage III Non-Small Cell Lung Cancer - Merck KGaA Press release from 12 Sept 2014
  21. ↑ Startschuss für innovative Brustkrebs-Impfstudie ABCSG-34
  22. ↑ ABCSG 34: Randomisierung beendet!
  23. ↑ Merck KGaA Annual Report 2013
  24. ↑ Oncothyreon Annual Report 2013 (Form 10-K)
  25. ↑ ClinicalTrials.gov
  26. ↑ The Primary Completion Date is defined as the date when the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome.
  27. ↑ All References related to this table can be found in the section "Overview and results of all trials"
  28. ↑ Oncothyreon's 8-K SEC filing from Aug 18, 2014
  29. ↑ Merck Discontinues Clinical Development Program of Tecemotide as a Monotherapy in Stage III Non-Small Cell Lung Cancer - Merck KGaA Press release from 12 Sept 2014
  30. ↑ Oncothyreon’s Annual Report 2013 (Form 10-K)
  31. ↑ Oncothyreon’s Annual Report 2013 (Form 10-K)
  32. ↑ Merck KGaA Annual Report 2013
  33. ↑ Merck Serono Investor & Analyst Day 2014 - Stefan Oschmann’s presentation - Slide 6 - 18 Sept 2014
  34. ↑ Oncothyreon’s Annual Report 2013 (Form 10-K)
  35. ↑ Oncothyreon’s Annual Report 2013 (Form 10-K)
  36. ↑ Oncothyreon’s Annual Report 2013 (Form 10-K)
  37. ↑ US Patent 6,600,012, Agrawal et al., Lipid-modified MUC-1 derivatives
  38. ↑ Palmer, M., Parker, J., Modi, S., Butts, C., Smylie, M., Meikle, A., Kehoe, M., MacLean, G., Longenecker, M. (2001) Phase I Study of the BLP25 (MUC1 Peptide) Liposomal Vaccine for Active Specific Immunotherapy in Stage IIIB/IV Non–Small-Cell Lung Cancer. Clinical Lung Cancer 3, 49–57. doi:10.3816/CLC.2001.n.018
  39. ↑ Oncothyreon's 8-K SEC filing from Aug 18, 2014
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