Tecemotide

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. 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. In 2008, Merck KGaA acquired the manufacturing rights for Tecemotide from Oncothyreon. 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.

The antigen: Tecemotide

Nonproprietary/generic names:

International Nonproprietary Name (INN): Tecemotide

United States Adopted Name (USAN): Emepepimut-S

Formerly known as:

BLP25 (Biomira lipopeptide 25) or EMD 531444

Function:

Tecemotide is the antigen of the cancer vaccine

Tecemotide is a synthetic lipopeptide 27 amino acids long. The first 25 amino acids of tecemotide are derived from the mucin 1 (MUC1) sequence:

human mucin-1 (carcinoma-associated mucin, episialin, CD227)-(107-131)-peptide (sequence 40 times repeated) fusion protein with 6-N-hexadecanoyl-L-lysylglycine

Molecular formula:

C₁₂₄H₂₀₃N₃₃O₃₈

CAS Registry Number:

221214-84-2

Amino acid sequence (27 amino acids):

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)

The adjuvant: MPL

3-O-Deacyl-4’-Monophosphoryl lipid A (MPL) is the adjuvant in the cancer vaccine. 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:

Non-specific immune stimulus

Stimulates macrophage activation

Stimulates antigen-presenting cells (APCs) through the toll-like receptor 4 (TLR-4)

The carrier: Lipids

Lipids:

Cholesterol, dimyristoyl phosphatidylglycerol (DMPG) and dipalmitoyl phosphatidylcholine (DPPC)

Function:

Structure of the liposome

Enhances uptake by APCs

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.

Overview and results of all trials

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

Overview of completed trials

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

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

On August 18, 2014, Oncothyreon 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.

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

the supply of ongoing investigator-sponsored NSCLC trials (non-monotherapy studies)

Merck’s own tecemotide trials in indications other than NSCLC (prostate cancer, colorectal cancer)

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.

Risks related to patent situation

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

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."

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]."

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.

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.

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.

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).