Merck & Co and Seattle Genetics have signed an exclusive licensing and co-developing agreement to globally develop and commercialize ladiratuzumab vedotin an investigational antibody-drug conjugate (ADC) targeting LIV-1, which is currently in phase II clinical trials for breast cancer and other solid tumors.

Most metastatic breast cancers express LIV-1, which also has been detected in several other cancers, including lung, head, and neck, esophageal, and gastric.  The investigational agent uses Seattle Genetics’ proprietary ADC technology and consists of a LIV-1-targeted monoclonal antibody linked to a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker. This drug is designed to bind to LIV-1 on cancer cells and release the cell-killing agent into target cells upon internalization. This last step drives antitumor activity through cytotoxic cell killing, induces immunogenic cell death (ICD). Ladiratuzumab vedotin may also cause antitumor activity through other mechanisms, including activation of an immune response by induction of immunogenic cell death.[1]

Strategic collaboration
The strategic oncology collaboration includes a broad joint development program evaluating ladiratuzumab vedotin as monotherapy and in combination with Merck’s anti-PD-1 therapy pembrolizumab (Keytruda®; Merck & Co) in metastatic triple-negative breast cancer (mTNBC), hormone receptor-positive breast cancer, and other LIV-1-expressing solid tumors.

There are currently no curative treatments for patients diagnosed with metastatic triple-negative breast cancer. The prognosis for this disease is very poor.

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One of the emerging and promising treatment options may include an anti-programmed death-ligand 1 (PD-L1) agents in combination with chemotherapy.  In clinical studies, ladiratuzumab vedotin monotherapy was well tolerated and demonstrated encouraging antitumor activity in patients with mTNBC.

Investigators believe that by combining ladiratuzumab vedotin with pembrolizumab may result in complementary, as well as a synergistic, activity through ladiratuzumab vedotin-induced ICD that creates a microenvironment favorable for enhanced anti-PD-L1 activity.

Co-commercialize
Merck & Co and Seattle Genetics have agreed to equally collaborate and equally share costs on the global development of ladiratuzumab vedotin and other LIV-1-targeting ADCs. They have also agreed to jointly develop and share future costs and profits for ladiratuzumab vedotin on a 50:50 basis worldwide.

The companies will co-commercialize in the U.S. and Europe. Seattle Genetics will be responsible for marketing applications for approval in the U.S. and Canada and will record sales in the U.S., Canada, and Europe. Merck will be responsible for marketing applications for approval in Europe and in countries outside the U.S. and Canada and will record sales in countries outside the U.S., Europe, and Canada.

Under the terms of the agreement, Seattle Genetics will receive a U.S. $ 600 million upfront payment and Merck will make a U.S. $1.0 billion equity investment in 5.0 million shares of Seattle Genetics common stock at a price of US $ 200 per share. In addition, Seattle Genetics is eligible for progress-dependent milestone payments of up to $ 2.6 billion, including US $850 million in development milestones and US $1.75 billion in sales milestones.

Together with the upfront payment, equity investment proceeds, and potential milestone payments, Seattle Genetics is eligible to receive up to $4.2 billion.

The closing of the equity investment is contingent on the completion of the review under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 (HSR Act).

“Collaborating with Merck on ladiratuzumab vedotin will allow us to accelerate and broaden its development program in breast cancer and other solid tumors, including in combination with Merck’s pembrolizumab, while also positioning us to leverage our U.S. and European commercial operations,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

Second program
In addition to a licensing and co-development of ladiratuzumab vedotin, the companies signed a separate agreement in which Seattle Genetics grants Merck an exclusive license to commercialize tucatinib (Tukysa®), a small molecule tyrosine kinase inhibitor, for the treatment of HER2-positive cancers, in Asia, the Middle East, and Latin America, and other regions outside of the U.S., Canada, and Europe. Seattle Genetics will receive U.S. $ 125 million from Merck as an upfront payment and is eligible for progress-dependent milestones of up to U.S. $ 65 million.

Tucatinib is an oral, small-molecule tyrosine kinase inhibitor (TKI) of HER2, a protein that contributes to cancer cell growth. The drug, in combination with trastuzumab and capecitabine, was approved by the U.S. Food and Drug Administration (FDA) in April 2020 for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Licensing agreement
As part of the agreement, Merck receives exclusive rights to commercialize tucatinib in Asia, the Middle East and Latin America, and other regions outside of the U.S., Canada, and Europe. Seattle Genetics retains commercial rights and will record sales in the U.S., Canada, and Europe. Merck will be responsible for marketing applications for approval in its territory, supported by the positive results from the HER2CLIMB clinical trial.

Global development
As part of the agreement, Merck will also co-fund a portion of the tucatinib global development plan, which encompasses several ongoing and planned trials across HER2-positive cancers, including breast, colorectal, gastric, and other cancers set forth in a global product development plan. Seattle Genetics will continue to lead ongoing tucatinib global development planning and operational execution. Merck will solely fund and conduct country-specific clinical trials necessary to support anticipated regulatory applications in its territory.

Seattle Genetics will receive U.S. $125 million as an upfront payment from Merck.  The company is also eligible to receive progress-dependent milestones of up to U.S. $65 million. Seattle Genetics will also receive U.S. $85 million in prepaid research and development payments to be applied to Merck’s global development funding obligations. In addition, Seattle Genetics would receive tiered royalties on sales of tucatinib in Merck’s territory.

The financial impact of these collaborations is not included in Seattle Genetics’ 2020 guidance.

New about the strategic agreement became public only hours after Gilead Sciences announced its acquisition of Immunimedics, in which Gilead gets access to Immunomedics ADC technology and sacituzumab govitecan (Trodelvy™; Immunomedics), an anti-Trop-2 ADC that is under review at the FDA as a third-line treatment for mTNBC.

The agreement between Merck & Co and Seattle Genetics and the acquisition of Immunmomedics by Gilead is the start of a new chapter in the history of Immunomedics and Seattle Generics, which, only a few years back, had a joint partnership which ultimately failed.

“The strategic collaboration for tucatinib will help us reach more patients globally and benefit from the established commercial strength of one of the world’s premier pharmaceutical companies,” Seattle Genetics’ Clay Siegall noted.

“These two strategic collaborations will enable us to further diversify Merck’s broad oncology portfolio and pipeline, and to continue our efforts to extend and improve the lives of as many patients with cancer as possible,” said Roger M. Perlmutter, M.D., Ph.D., President, Merck Research Laboratories.

“We look forward to working with the team at Seattle Genetics to advance the clinical program for ladiratuzumab vedotin, which has shown compelling signals of efficacy in early studies, and to bring tucatinib to even more patients with cancer around the world,” Perlmutter concluded.

Drug description
Ladiratuzumab vedotin [Drug map]

Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co) [Prescribing Information]
Tucatinib (Tukysa®; Seattle Genetics) [Prescribing Information]
Sacituzumab govitecan (Trodelvy™; Immunomedics) [Prescribing Information]

Clinical trials
Safety and Efficacy of SGN-LIV1A Plus Pembrolizumab for Patients With Locally-Advanced or Metastatic Triple-Negative Breast Cancer – NCT03310957
A Safety Study of SGN-LIV1A in Breast Cancer Patients – NCT01969643
Safety and Efficacy of SGN-LIV1A Plus Pembrolizumab for Patients With Locally-Advanced or Metastatic Triple-Negative Breast Cancer – NCT03310957
A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Patients With Advanced or Metastatic HER2+ Breast Cancer (HER2CLIMB-02) – NCT03975647
T-DM1 and Tucatinib Compared With T-DM1 Alone in Preventing Relapses in People With High Risk HER2-Positive Breast Cancer, the CompassHER2 RD Trial – NCT04457596
Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer (Mountaineer) – NCT03043313
Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer (MOUNTAINEER-02) – NCT04499924
Tucatinib Plus Trastuzumab and Oxaliplatin-based Chemotherapy for HER2+ Gastrointestinal Cancers – NCT04430738
A Study of Tucatinib Plus Trastuzumab Deruxtecan in HER2+ Breast Cancer – NCT04539938
Tucatinib in COmbination With Pembrolizumab And TrastuZumab in Women With HER2-Positive Breast Cancer Brain Metastases (TOPAZ) – NCT04512261

Reference
[1] Ladiratuzumab Vedotin (SGN-LIV1A) in Triple Negative Breast Cancers Shows a 29% ORR at the Recommended Dose in Heavily Pretreated Disease. J. Antibody-drug conjugates; December 7, 2017 [Article]
[2] Han HS, Alemany CA, Brown-Glaberman UA, Pluard TJ, Sinha R, Sterrenberg D, Albain KS, Basho RK, Biggs D, Boni V, Diab S, Tsai ML, et al. SGNLVA-002: Single-arm, open label phase Ib/II study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer. Journal of Clinical Oncology 2019 37:15_suppl, TPS1110-TPS1110 [Article]