Tecemotide

Last updated
Tecemotide
Vaccine description
Target MUC1
Vaccine type Protein subunit
Clinical data
Other namesEmepepimut-S; Stimuvax; BLP25; EMD 531444; L-BLP25; BLP25 liposomal vaccine
Identifiers
CAS Number
UNII
Chemical and physical data
Formula C124H203N33O38

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 to a rejection of tumor tissue expressing the MUC1 antigen. [1]

Contents

Collaboration

Tecemotide was developed – until Clinical trial phase II – by the Canadian biotech company Biomira Inc., which changed its company name to Oncothyreon Inc. in 2007. [2] Oncothyreon is now located in Seattle, Washington, and it changed its name to SGEN after a merger and acquisition in March 2018.[ citation needed ]

In 2001, Merck KGaA, of Darmstadt, Germany, entered into a collaboration and supply agreement with Biomira. In 2007, Merck KGaA acquired the exclusive worldwide marketing rights from Biomira, and Merck KGaA has since then been 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 Company, of Japan, acquired a co-development and co-marketing license for tecemotide in Japan; Ono paid Merck KGaA 5 million euros. [5]

Composition

Tecemotide is a synthetic lipopeptide that is 27 amino acids long. Its molecular formula is C124H203N33O38, and its amino acid sequence is S T A PPAH G VTSAPDTRPAPGSTAPPKG. The first 25 amino acids of tecemotide are derived from the mucin 1 (MUC1, carcinoma-associated mucin, episialin, or CD227) sequence. The 26th modified amino acid, K, is palmityl-lysine (N6-(1-oxohexadecyl)-L-lysine), and the 27th is glycine. [6]

Structure of the cancer vaccine

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). Stimuvax 01.png
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).

In the investigational therapeutic cancer vaccine (formerly known as Stimuvax, L-BLP25, BLP25 liposomal vaccine or BLP25 liposome vaccine), the antigen tecemotide is anchored — together with the adjuvant 3-O-deacyl-4′-monophosphoryl lipid A (MPL) — in the membrane of the liposome made from the lipids cholesterol, dimyristoyl phosphatidylglycerol (DMPG), and dipalmitoyl phosphatidylcholine. MPL is a derivative of the lipid A molecule found in the membrane of Gram-negative bacteria used as an adjuvant to initiate a non-specific immune stimulus, thereby stimulating the activation of antigen-presenting cells (APCs) through the toll-like receptor 4 (TLR-4) as well as macrophages. MPL is also used as an adjuvant in other vaccines, like Cervarix, a vaccine against certain types of cancer-causing human papillomavirus (HPV). [1]

The precise mixture of lipids in the vaccine, as well as providing the structure of the liposome, is also formulated to enhance the uptake of the vaccine by the aforementioned antigen-presenting cells. [7]

The cancer vaccine is a lyophilized powder, which is formulated to contain 300 μg of tecemotide and 150 μg of MPL per vial. [1]

Clinical trials

Overview and results of all trials

Tecemotide clinical trials (as of September 2, 2014) [8] sorted by (estimated) primary completion date: [9]

Clinical trials:

Lung cancer, Breast cancer, Prostate cancer, Colorectal cancer, and Multiple myeloma

NCT Number /
Title
Other IDsStart Date(Estimated) Primary Completion DateRecruitmentConditionsInterventionsPhasesEnrollment (Patients)Sponsor / Collaborators
Clinical trial number NCT00157209 for "Phase IIb Randomized Controlled Study of BLP25 Liposome Vaccine for Immunotherapy of Non-Small Cell Lung Cancer" at ClinicalTrials.gov B25-LG-304 / EMR 63325-005August 2000March 2006CompletedLung Neoplasms, Carcinoma, Non-Small-Cell LungBiological: BLP25 Liposome Vaccine plus best supportive care; Other: Best Supportive Care (BSC)Phase 2171Merck KGaA
Results: A Phase IIb clinical trial of 171 patients with inoperable stage IIIb non-small-cell lung cancer (NSCLC), in which tecemotide showed a trend towards extending median overall survival from 13.3 months for patients receiving best supportive care (BSC) to 30.6 months for patients receiving tecemotide plus BSC. Although this represents a subgroup analysis that is not statistically significant (with a nonsignificant P-value: p = 0.16), the magnitude of the difference and its durability over a prolonged period of follow up suggest an efficacy signal for the vaccine and would support further testing of tecemotide in a definitive phase III trial. Reported side effects included mild-to-moderate flu-like symptoms, gastrointestinal disturbances, and mild injection-site reactions. [10] Butts C, Maksymiuk A, Goss G, Soulières D, Marshall E, Cormier Y, et al. (September 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 (9): 1337–1342. doi:10.1007/s00432-011-1003-3. PMID   21744082. S2CID   25108866.
NCT00157196
Safety Study of BLP25 Liposome Vaccine in Non-Small Cell Lung Cancer Patients With Unresectable Stage III Disease
B25-LG-305 / EMR 63325-006April 2005September 2009CompletedCarcinoma, Non-Small-Cell Lung, Lung NeoplasmsBiological: BLP25 Liposome VaccinePhase 222Merck KGaA
NCT00925548
STRIDE - STimulating Immune Response In aDvanced brEast Cancer
STRIDE, EMR 200038–010, 2008-005544-17September 2009August 2010TerminatedBreast CancerBiological: Tecemotide (L-BLP25) and Hormonal Treatment, Biological: Placebo of tecemotide (L-BLP25) and Hormonal Treatment, Drug: cyclophosphamide, Drug: sodium chloride (NaCl)Phase 316EMD Serono
A thirty-site phase III trial (STRIDE) began in September 2009 on 900 women. The purpose of this study is to determine whether the addition of tecemotide to hormonal treatment is effective in prolonging progression-free survival in postmenopausal women with endocrine-sensitive inoperable locally advanced, recurrent, or metastatic breast cancer. [11] [12]

Results: The U.S. Food and Drug Administration (FDA) put the Phase III STRIDE trial on hold in March 2010 after a patient participating in a Phase II clinical trial with tecemotide in patients with multiple myeloma developed encephalitis. [13] The study was terminated in August 2010 (16 patients were enrolled in the study).

NCT01094548
Study of Stimuvax in Patients With Slowly Progressive Multiple Myeloma With no Symptoms and Who Have Had no Chemotherapy
EMR63325-008February 2008February 2011CompletedMultiple MyelomaBiological: L-BLP25, cyclophosphamide prior to first vaccination, Biological: L-BLP25Phase 234Merck KGaA
NCT00409188
Cancer Vaccine Study for Unresectable Stage III Non-small Cell Lung Cancer
START, EMR 63325-001January 2007August 2012CompletedNon-small Cell Lung CancerBiological: Tecemotide (L-BLP25), Biological: PlaceboPhase 31513EMD Serono, Merck KGaA
Results: The primary endpoint of overall survival was not met in the START trial. [14] However, the exploratory subgroup analysis in the START trial generated a reasonable hypothesis to warrant additional study.Kolahdooz F, Jang SL, Corriveau A, Gotay C, Johnston N, Sharma S (October 2014). "Knowledge, attitudes, and behaviours towards cancer screening in indigenous populations: a systematic review". The Lancet. Oncology. 15 (11): e504–e516. doi:10.1016/S1470-2045(14)70508-X. PMID   25281469.
NCT01731587
Anti-cancDer MUC1-specific Immunotherapy for Unresectable Stage III Non-small Cell Lung Cancer
FINGERPRINT, EMR 63325–019, 2012-001435-31WithdrawnNon-small Cell Lung Cancer (NSCLC) Stage IIIOther: Biological: MUC1 peptide specific immunotherapy, Drug: Cyclophosphamide (CPA)Phase 10Merck KGaA
NCT00960115
Study of EMD531444 in Subjects With Stage III Unresectable Non-small Cell Lung Cancer (NSCLC) Following Primary Chemoradiotherapy
EMR063325-009December 2008May 2014CompletedNon-small Cell Lung CancerBiological: cyclophosphamide + EMD531444 + BSC, Biological: Saline + Placebo + BSCPhase 1, Phase 2205Merck KGaA, Merck Serono Co., Ltd., Japan
Results: The analysis of EMR 63325–009, a randomized, double-blind, placebo-controlled, Phase I/II study in Japanese patients with Stage III unresectable, locally advanced NSCLC who had received concurrent or sequential chemoradiotherapy (CRT), with a minimum of two cycles of platinum-based chemotherapy and radiation dose ≥50 Gy shows the following results: Of the patients included in the Phase II part of the study, the majority had received concurrent CRT. The results indicate that no effect has been observed for either the primary endpoint, overall survival (OS), or any of the secondary endpoints (progression-free survival [PFS], time to progression [TTP], and time to treatment failure). An analysis of the reported adverse events has not identified a clinically meaningful difference in the frequency between treatment groups. Merck Serono made the recommendation to stop the investigational treatment for patients in the EMR 63325-009 study in Japan. [15]
EudraCT: 2011-004822-85
A prospective, open, randomized, phase-II study of a therapeutic cancer vaccine (L-BLP25, Stimuvax) in the pre-operative treatment of women with primary breast cancer
ABCSG-34 / EMR 63325-603Jan 2012May 2014Active, not recruitingBreast CancerL-BLP25 (Stimuvax), Cyclophosphamide (CPA), LETROZOLE, EPIRUBICIN, DOCETAXELPhase 2400ABCSG (Austrian Breast & Colorectal Cancer Study Group)
Results:

8 May 2012 [16]

  • Enrollment expected to be completed in May 2014
  • First results available end of 2014

26 Sept 2014 [17]

  • Enrollment of 400 patients completed
NCT01507103
Tecemotide (L-BLP25) in Rectal Cancer
SPRINT, EMR063325-013, 2011-000847-25February 2012June 2014Active, not recruitingRectal CancerCyclophosphamide (CPA), Tecemotide (L-BLP25)Phase 2124Merck KGaA
NCT00828009
BLP25 Liposome Vaccine and Bevacizumab After Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Stage IIIA or Stage IIIB Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery
CDR0000632611, E6508December 2010January 2016RecruitingLung CancerBiological: bevacizumab, Biological: emepepimut-S, Drug: carboplatin, Drug: cyclophosphamide, Drug: paclitaxel, Radiation: radiation therapyPhase 255Eastern Cooperative Oncology Group, National Cancer Institute (NCI)
NCT01462513
L-BLP25 in Patients With Colorectal Carcinoma After Curative Resection of Hepatic Metastases
LICC01August 2011September 2016RecruitingColon Carcinoma, Rectum CarcinomaBiological: L-BLP25, Biological: PlaceboPhase 2159Johannes Gutenberg University Mainz, Dr. Carl Schimanski
NCT01496131
Tecemotide (L-BLP25) in Prostate Cancer
EMR 63325–015, BB-IND 7787October 2011August 2017RecruitingProstate CancerRadiation: Radiation therapy, Drug: Goserelin, Drug: Cyclophosphamide, Drug: Tecemotide (L-BLP25)Phase 248EMD Serono, National Cancer Institute (NCI)
NCT02049151
Tecemotide Following Concurrent Chemo-radiotherapy for Non-small Cell Lung Cancer
START2, EMR 63325–021, 2013-003760-30March 2014July 2018RecruitingCarcinoma, Non-Small-Cell LungDrug: Tecemotide, Drug: Placebo, Drug: Cyclophosphamide (CPA), Drug: Saline (sodium chloride)Phase 31002EMD Serono
NCT01423760
Collect Long-term Data on Subjects Following Participation in Previous EMD 531444 (L-BLP25 or BLP25 Liposome Vaccine) Clinical Trials
EMR 63325-011January 2012December 2019Enrolling by invitationNon-Small Cell Lung Cancer, Multiple MyelomaBiological: Tecemotide, Other: No intervention262Merck KGaA
NCT01015443
Cancer Vaccine Study for Stage III, Unresectable, Non-small Cell Lung Cancer (NSCLC) in the Asian Population
INSPIRE, EMR63325-012December 2009May 2020RecruitingNon-Small Cell Lung CancerBiological: Tecemotide (L-BLP25), Biological: PlaceboPhase 3500Merck KGaA
Note: Merck KGaA and Oncothyreon are not reporting in their annual reports on colorectal cancer trials and prostate cancer trials [18] [19]

Overview of completed trials

Overview of completed tecemotide trials (as of September 2, 2014) [20] where results have been published, sorted by primary completion date: [21]

IDPhaseIndicationStartPrimary
Completion
Date
Summary of the results [22]
EMR 63325-0052 NSCLC August 2000March 2006Subgroup analysis favorable.
START, EMR 63325-0013NSCLCJanuary 2007August 2012Primary endpoint not met. Subgroup analysis favorable.
EMR 63325-009 (Japan study)1, 2NSCLCDecember 2008May 2014Primary endpoint and secondary endpoints not met. Subgroup analysis not favorable.

Discontinued development

On August 18 and September 12, 2014, Oncothyreon [23] and Merck KGaA, respectively, reported that a randomized Phase 1/2 study, EMR 63325–009, of tecemotide compared to a 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. [24]

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) are listed in the following sections.[ citation needed ]

Efficacy

As published so far, primary end points have not been met in the clinical studies, and tecemotide has shown treatment effects only in statistical analyses of certain subgroups. [25]

Patent situation

Oncothyreon's patent protection for tecemotide in the U.S. was scheduled to expire in 2018. [26]

Human resources

In 2013, Merck KGaA reported 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." [27]

Merck KGaA further reported with respect to its pharma division, Merck Serono: "Over 80% of the Merck Serono senior management positions [have been] replaced since 2011 [as of September 2014]." [28]

Novel technologies

Tecemotide is based on novel technologies, which may raise new regulatory issues that could delay or complicate regulatory approval. Additionally, as of 2013, the FDA had 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. [29]

Manufacture

Merck KGaA currently relies on third-party manufacturers to supply the product candidate: On Baxter International for the manufacture of tecemotide, and on GlaxoSmithKline plc (GSK) for the manufacture of the adjuvant in tecemotide, monophosphoryl lipid A (MPL). As of 2013, there was a risk that if tecemotide were not approved by 2015, GSK could terminate its obligation to supply MPL. In this case, Oncothyreon would have had to 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. [30]

Competition

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, 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. [31]

Drug development cost

The costs spent on 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 the full cost of bringing a new drug to market – from discovery through clinical trials to approval – is complex and controversial.[ citation needed ]

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

Timeline

DateEvent
May 1998Biomira files a BLP25 (tecemotide) patent [32]
May 2001Biomira licenses BLP25 (tecemotide) to Merck KGaA
Aug 2001Biomira publishes results of a Phase I study of the BLP25 (tecemotide)Palmer M, Parker J, Modi S, Butts C, Smylie M, Meikle A, et al. (August 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 (1): 49–57, discussion 58. doi:10.3816/clc.2001.n.018. PMID   14656392.
Mar 2006Results of the Phase IIb Study (EMR 63325-005): Subgroup analysis favorable
Aug 2007Merck KGaA acquires worldwide marketing rights for tecemotide from Oncothyreon and will be entirely responsible for the further clinical development of tecemotide
Sep 2007Biomira changes company name to Oncothyreon
Dec 2008Merck KGaA acquires manufacturing rights for tecemotide from Oncothyreon
Dec 2009INSPIRE study (EMR63325-012) started. Estimated primary completion date is May 2020
Oct 2011Ono Pharmaceutical acquires a co-development and co-marketing license for tecemotide in Japan
Dec 2012Results of the START study (EMR 63325-001): Primary endpoint not met. Subgroup analysis favorable
Mar 2014START2 study (EMR 63325-021) started. Estimated primary completion date is July 2018
Aug 2014Results of the Japan study (EMR 63325-009): Primary endpoint and secondary endpoints not met. Subgroup analysis not favorable [33]
Sep 2014Merck KGaA terminates the NSCLC development

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References

  1. 1 2 3 4 Goss G, Anderson H, Maksymiuk A, Vergidis D, Soulieres D, Cormier Y, et al. (September 2009). "BLP25 liposome vaccine (L-BLP25): long-term safety results from a phase IIb study of patients with stage IIIB and IV non-small-cell lung cancer (NSCLC) treated for 2 years or more" (PDF). Journal of Thoracic Oncology. 4 (9). Philadelphia: Lippincott Williams & Wilkins: S681. Archived from the original (PDF) on 17 October 2014.
  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. WHO Drug Information, Vol. 26, No. 4, 2012; Proposed INN: List 108
  7. Wurz GT, Kao CJ, Wolf M, DeGregorio MW (2015-01-27). "Tecemotide: an antigen-specific cancer immunotherapy". Human Vaccines & Immunotherapeutics. 10 (11): 3383–3393. doi:10.4161/hv.29836. PMC   4514140 . PMID   25483673.
  8. ClinicalTrials.gov
  9. 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.
  10. Butts C (August 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 .
  11. Merck KGaA to test Stimuvax in breast cancer trial (FierceVaccines) [usurped]
  12. UPDATE 2-Merck to test Stimuvax cancer drug in Phase III (Thomson Reuters)
  13. Merck KGaA press release from June 17, 2010
  14. 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)
  15. 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
  16. Startschuss für innovative Brustkrebs-Impfstudie ABCSG-34
  17. ABCSG 34: Randomisierung beendet!
  18. Merck KGaA Annual Report 2013
  19. Oncothyreon Annual Report 2013 (Form 10-K)
  20. ClinicalTrials.gov
  21. 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.
  22. All references related to this table can be found in the section "Overview and results of all trials"
  23. Oncothyreon's 8-K SEC filing from Aug 18, 2014 Archived August 21, 2014, at the Wayback Machine
  24. 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
  25. Oncothyreon's Annual Report 2013 (Form 10-K)
  26. Oncothyreon's Annual Report 2013 (Form 10-K)
  27. Merck KGaA Annual Report 2013
  28. Merck Serono Investor & Analyst Day 2014 - Stefan Oschmann's presentation - Slide 6 - 18 Sept 2014
  29. Oncothyreon's Annual Report 2013 (Form 10-K)
  30. Oncothyreon's Annual Report 2013 (Form 10-K)
  31. Oncothyreon's Annual Report 2013 (Form 10-K)
  32. US Patent 6,600,012, Agrawal et al., Lipid-modified MUC-1 derivatives
  33. Oncothyreon's 8-K SEC filing from Aug 18, 2014