Merck & Co (MSD) has agreed to acquire VelosBio, a privately held clinical-stage biopharmaceutical company, for U.S. $ 2.75 billion in cash, subject to certain customary adjustments. The closing of the transaction, which is subject to approval under the Hart-Scott-Rodino Antitrust Improvements Act and other customary conditions, is expected by the end of 2020.
VLS-101 is an investigational ADC that includes the anti-ROR1 antibody cirmtuzumab (formerly UC-961), a humanized IgG1 antibody (mAb) linked to monomethyl auristatin E (MMAE). After cirmtuzumab binds to ROR1 on cancer cells, the ADC is designed to enter these targeted cells and release MMAE to destroy the cancer cells. Photo courtesy VelosBio. Used with permission.The acquisition is expected to strengthens the Merck’s oncology pipeline by adding VelosBio lead investigational candidate is VLS-101, an antibody-drug conjugate (ADC) targeting receptor tyrosine kinase-like orphan receptor 1 (ROR1).
ROR1 is an onco-embryonic transmembrane receptor with tightly controlled expression during development. It is present at high levels on the cell surface of multiple tumor types but not on normal adult tissues. Hematological malignancies are often ROR1-positive (ROR1+), including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL).[1]
The unique pattern of expression of ROR1 makes it a tumor-specific therapeutic target.
Activation of ROR1 by binding its ligands such as Wnt5a results in increased intracellular signaling, tumor growth and survival, enhanced cancer cell stemness and epithelial mesenchymal transition.
The anti-ROR1 antibody, cirmtuzumab (formerly UC-961), a humanized IgG1 antibody (mAb), binds with high affinity to a specific extracellular epitope of human ROR1 receptor and can block Wnt5a-induced ROR1 signaling. [2]
Preclinical studies document that cirmtuzumab does not react with normal adult human tissues and selectively binds to tumor cells. Thes studies also found pharmacokinetic (PK) volume distribution in primates consistent with a lack of off-target binding to normal tissues. Because of its high specificity, rapid internalization, and trafficking to lysosomes, cirmtuzumab appears ideally suited to serve as the targeting moiety for an anti-ROR1 antibody-drug conjugate (ADC)[3]
VLS-101
VLS-101 is an investigational ADC which includes a ROR1 targeting antibody linked to monomethyl auristatin E (MMAE). After cirmtuzumab binds to ROR1 on cancer cells, the ADC is designed to enter those cells and release MMAE to destroy the cancer cells.
In pre-clinical mouse models of human hematologic malignancies and solid tumors, VLS-101 showed robust antitumor activity. VLS-101 is in clinical development for patients with previously treated hematologic malignancies and solid tumors. The U.S. Food and Drug Administration has granted VLS-101 orphan drug and fast track designations for the treatment of MCL.
VelosBio’s VLS-101 is currently being evaluated in a Phase I and a Phase II clinical trials.
VLS-101 is an investigational antibody-drug conjugate (ADC) targeting cancers that commonly express receptor tyrosine kinase-like orphan receptor 1 (ROR1). The ADC includes a humanized monoclonal antibody targeting ROR1, a proteolytically cleavable linker, and the anti-microtubule cytotoxin, monomethyl auristatin E (MMAE). The linker-toxin combination, also known as vedotin, is already used in FDA-approved and commercially available ADCs that target other tumor antigens. VLS-101 binds to ROR1-expressing tumor cells, resulting in internalization of the ADC-ROR1 complex. Within these tumor cells, lysosomal enzymes release the cytotoxin (ie, MMAE). Binding of MMAE to tubulin disrupts the microtubule network within the tumor cell, subsequently inducing cell-cycle arrest and apoptotic tumor cell death. In preclinical trials VLS-101 has demonstrated in vivo activity, including complete regression of tumors, in models of hematologic malignancies and solid tumors.Photo courtesy VelosBio. Used with permission.“At Merck, we continue to bolster our growing oncology pipeline with strategic acquisitions that both complement our current portfolio and strengthen our long-term growth potential,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.
“Pioneering work by VelosBio scientists has yielded VLS-101, which in early studies has provided notable evidence of activity in heavily pretreated patients with refractory hematological malignancies, including mantel cell lymphoma and diffuse large B-cell lymphoma.”
Evaluation in solid tumors
In October 2020, VelosBio announced the initiation of a Phase II clinical trial (NCT04504916) to evaluate VLS-101 for the treatment of patients with solid tumors, including patients with triple-negative breast cancer (TNBC), hormone receptor-positive and/or HER2-positive breast cancer, and non-squamous non-small-cell lung cancer (NSCLC).
In early clinical trials, VLS-101 demonstrated a manageable safety profile and early signs of anti-tumor activity.
Results of a Phase I clinical trial, to be presented virtually at the 62nd American Society of Hematology Annual Meeting (December 5-8, 2020), showed that VLS-101 resulted in objective clinical responses, including complete responses, in 47% (n=7/15) of patients with mantle cell lymphoma (MCL) and 80% (n=4/5) of patients with diffuse large B-cell lymphoma.[4]
Patients in this Phase I trial had been heavily pre-treated with other anticancer medications, and their cancers had failed to respond or had relapsed after initially responding to these other anticancer medications.
Pipeline of ADCs
In addition, VelosBio is developing a pre-clinical pipeline of next-generation ADCs and bispecific antibodies targeting ROR1 with the potential to complement VLS-101 by offering alternative methods of tumor cell killing.
“Merck is a recognized leader in oncology, and this acquisition reflects the hard work and commitment of all the employees at VelosBio in advancing the science of ROR1,” said Dave Johnson, founder and chief executive officer at VelosBio.
“We are very pleased that Merck has recognized the value of our first-in-class ROR1-directed investigational therapeutics. As part of Merck’s oncology pipeline, our lead product candidate, VLS-101, is now well positioned to achieve its maximum potential to benefit appropriate cancer patients in need,” Johnson concluded.
Clinical trials
A Phase 1 Dose-Escalation and Cohort-Expansion of VLS-101 in Hematologic Malignancies – NCT03833180
A Study of VLS-101 in Patients With Solid Tumors – NCT04504916
References
[1] Daneshmanesh AH, Porwit A, Hojjat-Farsangi M, Jeddi-Tehrani M, Tamm KP, Grandér D, Lehmann S, Norin S, Shokri F, Rabbani H, Mellstedt H, Österborg A. Orphan receptor tyrosine kinases ROR1 and ROR2 in hematological malignancies. Leuk Lymphoma. 2013 Apr;54(4):843-50. doi: 10.3109/10428194.2012.731599. Epub 2012 Oct 9. PMID: 22988987.
[2] Hasan MK, Yu J, Widhopf GF 2nd, Rassenti LZ, Chen L, Shen Z, Briggs SP, Neuberg DS, Kipps TJ. Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia. Blood. 2018 Jul 12;132(2):170-178. doi: 10.1182/blood-2017-12-819383. Epub 2018 Apr 20. PMID: 29678828; PMCID: PMC6043980.
[3] Mian YA, Widhopf II GF, Vo TT, Jessen K, Rassenti LZ, Kipps TJ. Development of Cirmtuzumab Antibody-Drug Conjugates (ADCs) Targeting Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) Blood (2018) 132 (Supplement 1): 1862. Online. Last accessed on November 5, 2020
[4] Vaisitti T, Jessen K, Lee TT2, Mira Ko, Arruga F, Vitale N, Braggio E. et al. VLS-101 is a Novel Therapeutic Antibody-Drug Conjugate (ADC) Targeting Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) in Richter Syndrome (RS). 161st ASH Annual Meeting | December 7-10, 2019 | Orlando, FL, USA | Poster #28561 [Download Poster]
Featured Image: Doctor talking to African American patient. Courtesy: © 2017 – 2020. Fotolia/Adobe. Used with permission.
