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08/03/23 11:08 PM
Seagen, Merck put $1.6B ADC collab on the back burner
adiratuzumab vedotin uses Seagen’s ADC technology—the gem of the Pfizer deal—to target LIV-1, which is expressed on most metastatic breast cancers.
Seagen is putting a phase 2 Merck & Co.-partnered antibody-drug conjugate on the shelf for now, nearly three years after signing on to a $1.6 billion partnership for the asset.
The company—which is in the process of being acquired by Pfizer—briefly noted in a second-quarter earnings filing Thursday that ladiratuzumab vedotin, or LV, is being deprioritized. Merck confirmed in an email Thursday afternoon that the company is in the process of discontinuing the program.
"LV has been shown to be clinically active with a tolerable safety profile, however, the emerging treatment landscape with newer therapeutics introduces a higher efficacy threshold," Seagen said in a statement to Fierce Biotech.
Merck in September 2020 ponied up $600 million for the ADC, alongside a $1 billion investment in Seagen, at the time known as Seattle Genetics. The companies planned to co-develop LV in combination with Keytruda for breast cancer and other solid tumors. The therapy was in phase 2 testing at the time but little has been detailed about the clinical program since. LV could have been a rival to Gilead Sciences’ Trodelvy.
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"Several attempts have been made to optimize the profile of LV through combination therapy and varying the dosing regimens, which were insufficient to elevate the efficacy profile of LV to justify moving to a pivotal trial whether as a monotherapy or in combination with Keytruda," the Seagen statement said.
LV uses Seagen’s ADC technology—the gem of the Pfizer megadeal—to target LIV-1, which is expressed in most metastatic breast cancers as well as in melanoma, prostate, ovarian, uterine and cervical cancers.
Merck was rumored to be in the running to buy Seagen last year, but the deal—reportedly valued around $40 billion—stalled when the parties could not agree on the right price. Pfizer came out the victor with a $43 billion offer.
The Seagen statement noted that the collaboration agreement signed in 2020 is still active.
Merck did not return a request for comment on the future of the LV program as of publication.
08/04/23 4:17 AM
Immuno-Oncology 2.0: How Regeneron is Utilizing its Expertise in Antibodies to Lead the Next Wave of Combinatorial Approaches in Cancer Care
Israel Lowy, MD, PhD, Regeneron
Senior Vice President of Translational and Clinical Oncology at Regeneron
Amazingly, it is only a little more than a decade since the first approval of a checkpoint blockade antibody for the treatment of cancer, which has led to a paradigm shift in cancer treatment.1 Prior to that, despite prior occasional successes, there was a great deal of skepticism that the immune system could be harnessed to battle malignancy.2 Now immunotherapy (including checkpoint inhibitors, tumor-targeted CD3 bispecifics, personalized cellular therapies, and other modalities) is accepted as a fundamental pillar of cancer care, alongside surgery, radiation and chemotherapy.1,3
While recent advances in the field of immuno-oncology have been transformational, significant unmet need remains for new cancer treatments that increase survival, reduce progression and improve quality of life for patients.1
The Universe of Immune Oncology Approaches
Approaches to augmenting the immune response to fight cancer range from those that directly enhance specific anti-tumor antigen reactivity to those that indirectly augment immune system function.
Classic examples of the direct approach are tumor infiltrating lymphocytes (TILs) that were hypothesized to be enriched in T cells that recognize tumor antigens. The isolation of TILs or peripheral T cells, expansion with/without gene engineering, and return to patients is a variation of directed personalized cellular therapies that have been approved or are in development.4 Personalized cellular immunotherapies have garnered substantial attention in the past few years.
Examples of indirect approaches include the original “Coley’s toxins,” cytokine based therapies such as high-dose interleukin 2 or, most prominently, checkpoint blockade, particularly CTLA-4 as the first to reach the market followed closely by PD-1/PD-1 ligand (PD-L1) based treatments.5,6 Checkpoint inhibitors help release the brakes that tumor cells exploit to prevent the system from reacting to them and further enhance the ability of immune cells to recognize and eliminate those cancer cells from the body.7 Some tumors express significant amounts of PD-L1, which interacts with the PD-1 receptor on cytotoxic T cells to block T cell activation. Anti-PD-1 and anti-PDL1 therapies block the PD-1 and anti-PD-L1 receptors on the T cells, respectively, thus re-enabling T cell activation against the cancer cells. Anti-PD-1 treatments have been approved both as a monotherapy, as well as part of combination therapies, irrespective of PD-L1 expression, for a variety of cancers.8 Particularly, anti-PD-1 therapies are now a cornerstone in cancer treatment due to their ability to help overcome one of tumors’ greatest survival mechanisms: suppression of the immune system.1,9
Between the poles of direct and indirect mechanisms lie newer efforts to focus immune activation towards tumor antigens, including tumor vaccines, protein therapeutics such as CD3 bispecifics, or tumor targeted cytokines. In particular, CD3 redirecting bispecific agents bridge tumor antigens to T cells and have been approved in several hematologic malignancies and are in development in solid tumors.9,10
Regeneron’s Approach to Oncology
A major focus of our research is to better harness and complement the immune system’s mechanisms for targeting and eliminating cancer cells with greater specificity while sparing as many healthy cells as possible. Regeneron recognizes that one of the key principles for successful deployment of the immune system is multi-targeting, the notion that multiple effector arms or specificities in combination will be required for optimal and durable anti-tumor activity. This is a lesson learned from the ostensible original purpose of the immune system, namely, to protect organisms from infectious pathogens.1,11
Regeneron’s tradition of physician-scientist leadership and deep knowledge of human biology guides us to look at cancer differently than other biopharmaceutical companies, following the science to fuel continued innovation and enable the development of novel combinatorial therapies. We are actively working to harness the body’s natural abilities to fight cancer via the immune system in new ways.
In particular, we invested in developing a toolkit of agents that target different aspects of the immune system and lend themselves to facile combinations with the goal of deploying the most potent immune effector responses against cancer.
Laying the Foundation with Anti-PD-1 Research
Regeneron initiated efforts researching the PD-1 pathway, and we have applied this experience to identify additional investigational pathways with the potential to address unmet medical need.
Research focused on PD-1 inhibition has made great strides in overcoming the immunosuppressive mechanisms of cancer cells, and combination therapies have progressed our understanding of how to harness the immune system’s abilities to fight cancer. We believe there is more to be done.1 We are currently developing additional combinations of checkpoint inhibitors and bispecifics.
Building a Future of Immunotherapy with Bispecific Antibody Approaches
Bispecific antibodies utilize the multi-targeting function of antibodies to enhance existing methods of cancer cell destruction.1 Regeneron’s Veloci-Bi® platform builds upon our antibody expertise and allows us to create full-length bispecific antibodies with no linkers or artificial sequences.12 Bispecific antibodies can thus be generated to bind to a target of choice, such as a tumor cell marker, and manufactured as a potential anti-cancer therapeutic. Due to the absence of artificial linkers, the bispecific antibodies mimic the structure and function of monoclonal antibodies but bind to multiple targets to enhance immune system function and targeted destruction of cancer cells.1,13
Being able to research these multiple pathways under one roof provides flexibility to easily explore different combination approaches.
Delivering on the Clinical Potential in Oncology
For 35 years, Regeneron has remained steadfast in our mission to use the power of science to repeatedly bring new, life-transforming medicines to patients. We’re applying this end-to-end formula to oncology, with the goal of revolutionizing the way cancer is treated. We are pursuing research with the goal of enhancing the natural functions of the human immune system to fight cancer.
Ultimately, we are proud to stand at the forefront of innovation for novel treatments in oncology and are committed to utilizing therapeutic flexibility to pioneer potential new solutions for previously untreatable cancers.
References
1Dahlen E, Veitonmaki N, Norlen P. Bispecific antibodies in cancer immunotherapy. Ther Adv Vaccines Immunother. 2018; 6(1):3–17. doi: 10.1177/2515135518763280
2Dobosz P, Dzieciatkowski T. The Intriguing History of Cancer Immunotherapy. Front Immunol. 2019; 10:2965. doi: 10.3389/fimmu.2019.02965
3National Cancer Institute. Immunotherapy to Treat Cancer. Published September 24, 2019. Accessed April 9, 2023. www.cancer.gov/about-cancer/treatment/types/immunotherapy
4Paijens S, Vledder A, Bruyn M, Nijman H. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol. 2020;18(4):842–859. doi: 10.1038/s41423-020-00565-9
5Asao, H. Interleukin-2. Reference Module in Biomedical Sciences. 2014. doi: 10.1016/B978-0-12-801238-3.040587
6Szeto G, Finley S. Integrative Approaches to Cancer Immunotherapy. Trends Cancer. 2019;5(7);400-410. doi: 10.1016/j.trecan.2019.05.010.
7Papaioannou, NE, Beniata, OV, Vitsos P, Tsitsilonis O, Samara P. Harnessing the immune system to improve cancer therapy. Annals of Translational Medicine. 2016;4(14):261–261. doi.org/10.21037/atm.2016.04.01
8Jiang H, Ni H, Zhang P, Guo X, Wu M, Shen H, et al. Oncoimmunology, 10(1), 1943180. Doi: 10.1080/2162402X.2021.1943180
9KC, Miljkovic MD, Walkdmann TA. Cytokines in the Treatment of Cancer. J Interferon Cytokine Res. 2019;39(1):6–21. doi: 10.1089/jir.2018.0019
10Benonisson H, Altintas I, Sluijter M, Verploegen S, Labrijn AF, Schuurhuis DH, et al. CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory. Mol Cancer Ther. 2019;18(2):312–322. doi: 10.1158/1535-7163.MCT-18-0679
11Petrelli A, Giordano S. From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage. Current Medicinal Chemistry. 2008;15(5):422-432. doi: 10.2174/092986708783503212
12Data on file. Regeneron.com: Technology.
13Wu Z, Cheung NV. T cell engaging bispecific antibody (T-BsAb): From technology to therapeutics. Pharmacology & Therapeutics. 2018; 182:161–175. Doi: 10.1016/j.pharmthera.2017.08.005
UNB-23-04-0001 06/2023
© 2023 Regeneron Pharmaceuticals Inc. All rights reserved.
AUTHOR
Israel Lowy, MD, PhD, Regeneron
Senior Vice President of Translational and Clinical Oncology at Regeneron
@Regeneron
Israel Lowy, MD, PhD, Regeneron on LinkedIn
https://www.regeneron.com/
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