Merck Announces Phase 3 Trial Initiations for Four Investigational Candidates From its Promising Hematology and Oncology Pipeline

Global Phase 3 studies started for bomedemstat (LSD1 inhibitor), nemtabrutinib (BTK inhibitor), MK-2870 (anti-TROP2 ADC) and MK-5684 (CYP11A1 inhibitor)

Comprehensive clinical development programs being initiated for each investigational candidate

Demonstrates company’s commitment to research across novel mechanisms of action in hematologic neoplasms/malignancies, as well as lung, endometrial and prostate cancers

RAHWAY, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the initiation of pivotal Phase 3 trials for four of its investigational candidates from its diverse pipeline in hematologic malignancies and solid tumors. Global Phase 3 studies have been initiated and are actively enrolling for the following investigational candidates:

• Bomedemstat, an investigational orally available lysine-specific demethylase 1 (LSD1) inhibitor, being evaluated for the treatment of certain patients with essential thrombocythemia (ET);
• Nemtabrutinib, an investigational oral, reversible, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, being evaluated for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL);
• MK-2870, an investigational trophoblast cell-surface antigen 2 (TROP2)-directed antibody drug conjugate (ADC) being developed in collaboration with Kelun-Biotech, which is being evaluated for certain patients with non-small cell lung cancer (NSCLC) and certain patients with previously treated endometrial carcinoma;
• and MK-5684, an investigational CYP11A1 inhibitor being developed in collaboration with Orion, which is being evaluated for the treatment of certain patients with metastatic castration-resistant prostate cancer (mCRPC).

“These Phase 3 trial initiations for four of our investigational candidates represent a critical step forward in our efforts to advance potential treatment options for people with solid tumors and hematologic neoplasms and malignancies,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “We have a proud legacy of turning breakthrough science into medicines that save and improve lives around the world, and we are dedicated to continuing research to expand our broad portfolio of oncology therapeutics to continue to address unmet needs in cancer care.”

About Bomedemstat and MK-3543-006

Bomedemstat is an investigational orally available small molecule that inhibits LSD1, an enzyme that is potentially important for regulating the proliferation of hematopoietic stem cells and the maturation of progenitor cells. In non-clinical studies, bomedemstat demonstrated robust in vivo anti-tumor efficacy across a range of myeloid malignancies as a single agent and in combination with other therapeutic agents.

Merck has initiated the pivotal Phase 3 randomized MK-3543-006 clinical trial (NCT06079879) evaluating bomedemstat compared to best available therapy (BAT) as treatment in patients with ET who have an inadequate response to or are intolerant of hydroxyurea. Global recruitment of the trial has begun, with patients now enrolling.

MK-3543-006 is a Phase 3, global, randomized, open-label, active-comparator-controlled clinical study that is slated to enroll approximately 300 patients around the world. The primary endpoint of the study is durable clinicohematologic response (DCHR) rate, and key secondary endpoints include duration of clinicohematologic response (DOCHR), duration of hematologic remission (DOHR), disease progression rate and event free survival (EFS).

Bomedemstat has U.S. Food and Drug Administration (FDA) Orphan Drug and Fast Track Designation for the treatment of ET and myelofibrosis (MF), Orphan Drug Designation for the treatment of acute myeloid leukemia (AML) and Priority Medicines (PRIME) scheme designation by the European Medicines Agency (EMA) for the treatment of MF. Merck presented updated data from the Phase 2b MK-3543-003 trial, including first time genomic data, at the American Society for Hematology (ASH) Annual Meeting in December 2023. This is one of multiple Phase 2 clinical trials where bomedemstat is currently being evaluated alone and in combination for the treatment of myeloproliferative neoplasms (MPNs) such as ET, MF and polycythemia vera (PV).

About Nemtabrutinib and BELLWAVE-011

Nemtabrutinib is an investigational oral, reversible, non-covalent BTK inhibitor that suppresses oncogenic B-cell receptor signaling with activity against wild-type BTK and BTK pathway mutants. Nemtabrutinib aims to address a common mechanism of resistance with currently available irreversible, covalent BTK inhibitors by binding in an alternative way to the BTK protein.

Merck has initiated the pivotal Phase 3 randomized BELLWAVE-011 clinical trial (NCT06136559) evaluating nemtabrutinib versus investigator’s choice of ibrutinib or acalabrutinib in patients with previously untreated CLL and SLL. Global recruitment of the trial has begun, with patients now enrolling.

BELLWAVE-011 is a Phase 3, global, randomized, open-label, active-comparator-controlled clinical study that is slated to enroll approximately 1,200 patients around the world. The primary endpoints of the study are objective response rate (ORR) per Chronic Lymphocytic Leukemia (iwCLL) Criteria 2018 as assessed by Blinded Independent Central Review (BICR) and progression-free survival (PFS) per iwCLL Criteria 2018 as assessed by BICR. Key secondary endpoints include overall survival (OS) and duration of response (DOR) per iwCLL Criteria 2018 as assessed by BICR.

Merck is committed to research with nemtabrutinib across B-cell malignancies and is establishing a robust program of clinical trials under the name BELLWAVE. In addition to BELLWAVE-011, a Phase 3 study is currently underway in patients with previously untreated CLL and SLL without TP53 aberrations (BELLWAVE-008, NCT05624554).

About MK-2870 and MK-2870-004, MK-2870-007 and MK-2870-005

MK-2870 is an investigational ADC that consists of an antibody targeting TROP2 linked to a belotecan-derived payload. TROP2 is highly expressed in a variety of epithelial-derived tumors and can promote tumor cell proliferation, invasion and metastasis. TROP2 ADCs specifically target TROP2-expressing tumor cells to deliver cytotoxic effects and have shown encouraging anti-tumor activity in clinical studies.

Merck has initiated three pivotal Phase 3 clinical trials evaluating MK-2870 in which patients are now enrolling: MK-2870-004 (NCT06074588), MK-2870-007 (NCT06170788) and MK-2870-005 (NCT06132958).

MK-2870-004 is a Phase 3, global, randomized, open-label, active-comparator-controlled clinical study evaluating MK-2870 compared to chemotherapy (docetaxel or pemetrexed) for the treatment of previously treated advanced or metastatic NSCLC with EGFR mutations or other genomic alterations. The trial is slated to enroll approximately 556 patients around the world. The primary endpoints of the study are PFS and OS, and key secondary endpoints include ORR and DOR.

MK-2870-007 is a Phase 3, global, randomized, open-label, active-comparator-controlled clinical study evaluating MK-2870 in combination with KEYTRUDA^® (pembrolizumab) compared to KEYTRUDA alone in patients with metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. The trial is slated to enroll approximately 614 patients around the world. The primary endpoint of the study is OS, and key secondary endpoints include PFS, DOR and objective response (OR).

MK-2870-005 is a Phase 3, global, randomized, open-label, active-comparator-controlled clinical study evaluating MK-2870 compared to a treatment of physicians’ choice in patients with endometrial carcinoma who have received prior platinum-based chemotherapy and immunotherapy. The trial is slated to enroll approximately 710 patients around the world. The primary endpoints of the study are PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by BICR and OS. Key secondary endpoints include ORR per RECIST 1.1 as assessed by BICR and DOR per RECIST 1.1 as assessed by BICR.

MK-2870 was developed by Kelun-Biotech. Kelun-Biotech (6990.HK) is a holding subsidiary of Kelun Pharmaceutical (002422.SZ), which focuses on the R&D, manufacturing, commercialization and global collaboration of innovative biological drugs and small molecule drugs. Under a collaboration agreement, Kelun-Biotech has granted Merck the exclusive rights to develop, manufacture, and commercialize MK-2870 in all territories outside of Greater China. In addition to MK-2870-004, MK-2870-007 and MK-2870-005, Merck intends to rapidly advance the global clinical development program evaluating MK-2870 as a monotherapy and in combination with KEYTRUDA in various solid tumors.

About MK-5684 (ODM-208) and OMAHA1 and OMAHA2a

MK-5684 is an oral, non-steroidal and selective inhibitor of the CYP11A1 enzyme discovered and developed by Orion and is being investigated for the treatment of hormone-dependent cancers, such as prostate cancer. By inhibiting CYP11A1 enzyme activity, MK-5684 is designed to suppress the production of all steroid hormones and their precursors that may activate the androgen receptor signaling pathway.

Merck and Orion Corporation have initiated two pivotal Phase 3 clinical trials evaluating MK-5684 (ODM-208) in combination with hormone replacement therapy (HRT), for the treatment of certain patients with mCRPC. Patients are now enrolling in these two trials, named OMAHA1 (NCT06136624) and OMAHA2a (NCT06136650).

OMAHA1 is a randomized, open-label Phase 3 trial evaluating MK-5684 in combination with HRT for the treatment of patients with later-line mCRPC who have failed one prior new hormonal agent (NHA) and one or two prior taxanes compared to an alternative NHA (abiraterone or enzalutamide). The trial will enroll an estimated 1,200 patients around the world. The primary endpoints are OS and radiographic progression-free survival (rPFS) by androgen receptor ligand-binding domain (AR LBD) mutation status. Secondary endpoints include time to first subsequent therapy (TFST), ORR and DOR.

OMAHA2a is a randomized, open-label Phase 3 trial evaluating MK-5684 in combination with HRT for the treatment of patients with front-line mCRPC who have failed one prior NHA compared to physician’s choice of NHA (abiraterone or enzalutamide). The trial will enroll an estimated 1,500 patients around the world. The primary endpoints are OS and rPFS by AR LBD mutation status. Secondary endpoints include TFST, ORR and DOR.

Orion is a globally operating Finnish pharmaceutical company that develops, manufactures and markets human and veterinary pharmaceuticals and active pharmaceutical ingredients. The core therapy areas of their pharmaceutical R&D are oncology and pain.

Selected KEYTRUDA^® (pembrolizumab) Indications in the U.S.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

• stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
• metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.

See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA.

Contacts

Media:

Julie Cunningham

(617) 519-6264

Nikki Lupinacci

(718) 644-0730

Investor:

Peter Dannenbaum

(732) 594-1579

Damini Chokshi

(732) 594-1577

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