ulevostinag (MK-1454) / Merck (MSD) - LARVOL DELTA

Phase 1 and 2 Clinical Studies of the STING Agonist Ulevostinag With and Without Pembrolizumab in Participants With Advanced or Metastatic Solid Tumors or Lymphomas. (PubMed, Clin Cancer Res) - P1, P2 | "Intratumoral ulevostinag (±pembrolizumab) had manageable toxicity, dose-dependent pharmacokinetics, and evidence of STING activation and target engagement. Combination therapy showed antitumor activity in participants with untreated metastatic or unresectable, recurrent HNSCC."

Journal • P1 data • Breast Cancer • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CXCL10 • IFNG • IL6 • STING

Toward safer pharmaceutical manufacturing: Harnessing the power of diversity (ACS-Fall 2023) - "Green chemistry mindset encourages the discovery of novel chemical transformations that are more sustainable, economical, and safer to execute. In this presentation, a series of chemistry development examples including nemtabrutinib and ulevostinag will be discussed to illustrate how fearless generation of diverse ideas helped the process chemists at Merck to address safety challenges in drug substance development."

Discovery and process development of stimulator of interferon genes (STING) agonist MK-1454 (ACS-Fall 2023) - "The identification of an endogenous agonist of human STING, 2',3'-cGAMP, has prompted interest in discovery of novel STING agonists suitable for cancer treatment in clinic.We have discovered and developed the potent STING agonist MK-1454, which is being studied in Phase II clinical trials in patients with advanced/metastatic solid tumors or lymphomas and recurrent head and neck squamous cell carcinoma, both as a single agent and in combination with the anti-PD1 monoclonal antibody pembrolizumab. To address the synthesis of such a complex target molecule we sought to rely on innovative bond disconnections and application of the potential of biocatalysis. These investments paid off in not only a shortened synthetic sequence, but also produced several new synthetic methods and addresses the increased regulatory and environmental burden required for the commercial routes for active pharmaceutical ingredients."

Head and Neck Cancer • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • STING

Discovery and development of MK-1454, a therapeutic cyclic dinucleotide STING agonist (ACS-Sp 2023) - "The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. Finally, from these complex subunits, a novel thiophosphorylation reaction and a multi-step biocatalytic cascade enabled by the directed evolution of engineered enzymes were developed, providing a diastereoselective synthesis of this complex structure in unprecedented yield and efficiency."

Oncology • Solid Tumor

Accelerating drug development through innovation for the stereoselective synthesis of cyclic dinucleotide MK-1454 (ACS-Sp 2023) - "From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high-yielding cascade process. Overall, these developments and innovations led to vast reductions in waste production and substantial gains in sustainability, efficiency, and process safety."

Oncology

Biocatalytic, stereoselective synthesis of a cyclic dinucleotide MK-1454 (ACS-Sp 2023) - "This biocatalytic cascade obviated the need for protecting groups, tedious functional group manipulations, and wasteful chromatography, which resulted in a greener process. This talk will emphasize how biocatalysis can be harnessed to provide unique advantages to the synthesis complex molecular targets such as MK-1454."

Oncology • STING

Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas (ESMO 2018) - P1; "Combined MK-1454 plus pembro resulted in encouraging efficacy and an acceptable safety profile supporting continued development of the combination regimen."

Clinical • Combination therapy • IO biomarker • Late-breaking abstract • Monotherapy • P1 data • PD(L)-1 Biomarker • Lymphoma • Thyroid Gland Carcinoma • Triple Negative Breast Cancer

Study of Intratumoral (IT) Ulevostinag (MK-1454) in Combination With Intravenous (IV) Pembrolizumab (MK-3475) Compared to IV Pembrolizumab Alone as the First Line Treatment of Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) (MK-1454-002) (clinicaltrials.gov) - P2 | N=18 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed | N=200 ➔ 18 | Trial completion date: Apr 2023 ➔ Sep 2022 | Trial primary completion date: Apr 2023 ➔ Sep 2022

Combination therapy • Enrollment change • Monotherapy • Trial completion • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

A Unified Strategy to Fluorinated Nucleoside Analogues Via an Electrophilic Manifold. (PubMed, Org Lett) - "Initially developed to facilitate the manufacture of 3'-fluoroguanosine (3'-FG)─a substructure of anticancer therapeutic MK-1454─this strategy has been extended to the synthesis of a variety of 3'-fluoronucleosides. Finally, we demonstrate the utility of the 2'-ketonucleoside synthon as a platform for further diversification and suggest that this methodology should be broadly applicable to the discovery of novel nucleoside analogues."

Journal • Oncology

Photo-Oxidation Mechanisms in Liquid Pharmaceutical Formulations: The Overlooked Role of Singlet Oxygen Presented as a Case Study. (PubMed, Pharm Res) - "This work highlights the importance of understanding photochemical degradation of APIs in solution formulations and provides approaches which can better elucidate those mechanisms and thereby control strategies."

Journal

Cascades of Evolved Enzymes for the Synthesis of Complex Molecules. (PubMed, Angew Chem Int Ed Engl) - "This supports the goal of the chemical and pharmaceutical industries to move to more sustainable and environmentally friendly processes. Recently described outstanding examples include the biocatalytic cascade syntheses of the cyclic dinucleotide MK-1454, molnupiravir, and islatravir, as well as the efficient fixation of CO to make starch using an artificial enzyme cascade."

Journal • Review

pH-switchable extractants for host cell protein rejection in the cascaded biocatalytic synthesis of an active pharmaceutical ingredient (ACS-Fall 2022) - "Leveraging the rapid generation of modular acid-base pairs, we describe a pH-coupled extraction strategy relying on tertiary ammonium extractant switches for efficient purification and isolation of hydrophilic immuno-oncology drug candidate MK-1454 from an aqueous biocatalytic cascade containing crude E. coli cell lysates. We demonstrate this technique on >300 g scale to isolate MK-1454 with no detectable protein impurities for human administration in clinical trials."

Oncology

Study of Ulevostinag (MK-1454) Alone or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors or Lymphomas (MK-1454-001) (clinicaltrials.gov) - P1 | N=157 | Completed | Sponsor: Merck Sharp & Dohme Corp. | Active, not recruiting ➔ Completed | N=235 ➔ 157

Combination therapy • Enrollment change • Monotherapy • Trial completion • Breast Cancer • Cutaneous T-cell Lymphoma • Gastrointestinal Cancer • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD4

Holistic Analytical Characterization and Risk Assessment of Residual Host Cell Protein Impurities in an Active Pharmaceutical Ingredient (API) Synthesized by Biocatalysts. (PubMed, Biotechnol Bioeng) - "Although a lot of attentions have been focused on defining a universally acceptable limit for such impurities, the risks associated with residual HCPs on product quality, safety, and efficacy often need to be determined on a case-by-case basis taking into consideration the residual HCP profile in the product, the dose, dosage form, and administration route etc. Here we describe the unique challenges for residual HCP control presented by the biocatalytic synthesis of a Merck investigational stimulator of interferon genes protein (STING) agonist, MK-1454, which is a cyclic dinucleotide synthesized using E. coli cell lysate overexpressing cyclic GMP-AMP synthase (cGAS) as a biocatalyst...Although a lot of attentions have been focused on defining a universally acceptable limit for such impurities, the risks associated with residual HCPs on product quality, safety, and efficacy often need to be determined on a case-by-case basis taking into consideration the residual HCP..."

Journal • CGAS • STING

Discovery of MK-1454: A Potent Cyclic Dinucleotide Stimulator of Interferon Genes Agonist for the Treatment of Cancer. (PubMed, J Med Chem) - "Tumor shrinkage in mouse models that are intrinsically resistant to single-agent therapy was further enhanced when treating the animals with MK-1454 in combination with a fully murinized antimouse PD-1 antibody, mDX400. These data support the development of STING agonists in combination with pembrolizumab (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 therapy."

Journal • Oncology • STING

Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454. (PubMed, J Am Chem Soc) - "From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thorough understanding of the role transition metals play in bond formation."

Journal • STING

A kinase-cGAS cascade to synthesize a therapeutic STING activator. (PubMed, Nature) - P2 | "Here we describe the discovery and construction of an enzymatic cascade to MK-1454, a highly potent stimulator of interferon genes (STING) activator under study as an immuno-oncology therapeutic (ClinicalTrials.gov study NCT04220866 )...For the thiotriphosphate synthesis, three kinase enzymes were engineered to develop a non-natural cofactor recycling system in which one thiotriphosphate serves as a cofactor in its own synthesis. This study demonstrates the substantial capacity that currently exists to use biosynthetic approaches to discover and manufacture complex, non-natural molecules."

Journal • Oncology • STING

Study of Ulevostinag (MK-1454) Alone or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors or Lymphomas (MK-1454-001) (clinicaltrials.gov) - P1 | N=235 | Active, not recruiting | Sponsor: Merck Sharp & Dohme Corp. | Trial completion date: Oct 2022 ➔ Apr 2022 | Trial primary completion date: Oct 2022 ➔ Apr 2022

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Cutaneous T-cell Lymphoma • Gastrointestinal Cancer • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD4

Accelerating drug discovery and development through Innovation in green chemistry (ACS-Sp 2022) - "The impact of such innovations is demonstrated in our recent development of a one-pot enzymatic process for the production of MK-1454, a stimulator of interferon gene (STING) protein agonist for the treatment of cancer, and in a commercial-scale photobromination in flow for the production of Belzutifan (MK-6482), an FDA-approved first-in-class therapy for the treatment of patients with Von Hippel-Lindau (VHL) disease-associated tumors. In both examples, innovation in green chemistry has dramatically improved the synthetic efficiency and reduced the waste generation."

Oncology • Von Hippel-Lindau Syndrome • STING

[VIRTUAL] Phase II study of intratumoral MK-1454 plus pembrolizumab compared with pembrolizumab monotherapy as first-line treatment for metastatic or unresectable, recurrent head and neck squamous cell carcinoma (ESMO 2020) - P2 | "In KEYNOTE-048, which compared pembro ± chemotherapy with cetuximab + chemotherapy in patients with previously untreated metastatic or recurrent head and neck squamous cell carcinoma (HNSCC), pembro significantly prolonged OS as monotherapy in patients with a PD-L1 combined positive score (CPS) ≥1 and ≥20 and in combination with chemotherapy in patients with CPS ≥1 and ≥20 and in the total population. Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Clinical trial identification: 2019-003060-42; NCT04220866."

Clinical • Monotherapy • P2 data • Head and Neck Cancer • Hematological Malignancies • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • STING

Current status of intralesional agents in treatment of malignant melanoma. (PubMed, Ann Transl Med) - "This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid..."

Journal • Review • Gene Therapies • Immune Modulation • Inflammation • Melanoma • Oncology • Solid Tumor • CD40 • IL12A • MAGEA3 • TYRP1

Study of Intratumoral (IT) MK-1454 in Combination With Intravenous (IV) Pembrolizumab (MK-3475) Compared to IV Pembrolizumab Alone as the First Line Treatment of Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) (MK-1454-002) (clinicaltrials.gov) - P2; N=200; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Trial completion date: Sep 2023 ➔ Apr 2023; Trial primary completion date: Sep 2023 ➔ Apr 2023

Clinical • Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

Study of MK-1454 Alone or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors or Lymphomas (MK-1454-001) (clinicaltrials.gov) - P1; N=235; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • Cutaneous T-cell Lymphoma • Gastrointestinal Cancer • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD4

Study of Intratumoral (IT) MK-1454 in Combination With Intravenous (IV) Pembrolizumab (MK-3475) Compared to IV Pembrolizumab Alone as the First Line Treatment of Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) (MK-1454-002) (clinicaltrials.gov) - P2; N=200; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Recruiting ➔ Active, not recruiting

Enrollment closed • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

The Age of Cyclic Dinucleotide Vaccine Adjuvants. (PubMed, Vaccines (Basel)) - P1, P2 | "However, in October 2018, the first clinical data with Merck's CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro's CDN ADU-S100 monotherapy was also disappointing (NCT03172936)...Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans."

Clinical • Journal • Review • Hematological Malignancies • Infectious Disease • Oncology • Solid Tumor