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WO2025080767A1 - Schéma posologique de différenciation et d'entretien pour fhd 286 (inhibiteur de brg1/brm) - Google Patents

Schéma posologique de différenciation et d'entretien pour fhd 286 (inhibiteur de brg1/brm) Download PDF

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Publication number
WO2025080767A1
WO2025080767A1 PCT/US2024/050660 US2024050660W WO2025080767A1 WO 2025080767 A1 WO2025080767 A1 WO 2025080767A1 US 2024050660 W US2024050660 W US 2024050660W WO 2025080767 A1 WO2025080767 A1 WO 2025080767A1
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Prior art keywords
fhd
subject
cancer
dose regimen
pharmaceutically acceptable
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PCT/US2024/050660
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English (en)
Inventor
Jessica C. PIEL
Michael P. COLLINS
Astrid THOMSEN
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Foghorn Therapeutics Inc
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Foghorn Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure features a method of administering to a subject (i) a differentiation dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, and, following step (i), administering to the subject (ii) maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, wherein the differentiation dose regimen and the maintenance dose regimen together are effective to treat the cancer, and wherein the average daily dose during the differentiation dose regimen is at least 1 .25-fold higher than the average daily dose during the maintenance dose regimen.
  • the differentiation dose regimen comprises administering daily to the subject greater than 7.5 mg to 22.5 mg of FHD 286, or a pharmaceutically acceptable salt thereof
  • the maintenance dose regimen comprises administering daily to the subject from 1 .5 mg to 7.5 mg of FHD 286, or a pharmaceutically acceptable salt thereof.
  • the method can include a differentiation dose regimen that includes administering to the subject about 10 mg per day, about 12.5 mg per day, about 15 mg per day, about 17.5 mg per day, about 20 mg per day, or about 22.5 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof.
  • the differentiation dose regimen can include administration to the subject daily, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, once in fourteen days or once in twenty-eight days.
  • the differentiation dose regimen can include administration to the subject daily, about 10 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof.
  • the maintenance dose regimen can include administration of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject for a period of at least one month, at least 3 months, at least six months, or at least 12 months.
  • day 1 one time on day 1 and one or more times of any of the following days: day 2, day 3, day 4, day 5, day 6, day 7, day 8 day 9, day 10, day 11 , day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21 , day 22, day 23, day 24, day 25, day 26, day 27, or day 28).
  • the invention provides a method of treating hematological cancer in a subject, wherein the differentiation dose of FHD 286 (high dose) is administered at a dose between about
  • the differentiation dosing cycle is followed by the maintenance dosing cycle dosing cycle.
  • the differentiation-maintenance cycle is performed once, twice, or three times.
  • the invention features a method of treating hematologic cancer in a subject in need thereof, the method including (a) providing a subject previously treated with an anticancer agent to induce cell arrest and/or apoptosis in leukemic stem cells in the subject, and (b) administering to the subject a maintenance dose regimen of FHD 286, or a pharmaceutically acceptable salt thereof, sufficient to reduce the number of blast cells in the subject.
  • the method includes administering a maintenance dose regimen including an average daily dose between about 1.5 mg and about 7.5 mg per day of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject (e.g., between about 1 .5 mg and about 7.5 mg per day, between about 1 .5 mg and about 5 mg per day, or between about 1 .5 mg and about 2.5 mg per day).
  • the maintenance dose regimen can include administering to the subject about 1 .5 mg per day, 2.5 mg per day, 5.0 mg per day, about 7.5 mg per day of the FHD 286, or a pharmaceutically acceptable salt thereof.
  • the maintenance dosing cycle is optionally followed by a subsequent differentiation dosing cycle.
  • the differentiation-maintenance dosing cycle is performed once, twice, or three times.
  • the maintenance dosing cycle is optionally followed by a subsequent maintenance dosing cycle.
  • the maintenance-maintenance dosing cycle is performed once, twice, or three times.
  • the method includes at least 21 days, 28 days, 2 months, 3 months, 4 months, 6 months, 1 year, 2 years, 5 years, or 10 years of treatment.
  • the invention provides a method of treating hematological cancer in a subject, wherein the risk of developing differentiation syndrome is reduced in the subject relative to treatment with a high dose of FHD 286, or a pharmaceutically acceptable salt thereof, or relative to treatment with a low dose of FHD 286, or a pharmaceutically acceptable salt thereof, alone.
  • the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B- cell lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, diffuse large B cell lymphoma, or non-Hodgkin’s lymphoma.
  • the cancer is diffuse large B cell lymphoma (DLBCL).
  • the AML harbors an MLL-r mutation, an MLL PTD mutation, a DNMT3A mutation, an FLT3 mutation, an IDH1 mutation, an IDH2 mutation, an NPM1 mutation, a splicing factor mutation, a TP53 mutation, a CEBPA mutation, an AML-ETO fusion mutation, or a combination thereof.
  • the hematological cancer has or has been determined to have inv(3) mutation. In some embodiments, the hematological cancer has or has been determined to have 7/del(7q) mutation. In some embodiments, the hematological cancer has or has been determined to have SF3B1 mutation.
  • the invention provides a method of treating solid tumors in a subject, wherein the solid tumor is a tumor of the bladder, gastrointestinal tract, colon, breast, prostate, lung, kidney, liver, pancreas, ovary, head and neck, oral cavity, stomach, duodenum, small intestine, large intestine, anus, gall bladder, labium, nasopharynx, skin, uterus, male genital organ, urinary organs, and skin.
  • Solid tumors of non-epithelial origin include sarcomas, brain tumors, and bone tumors.
  • the melanoma is uveal melanoma, cutaneous melanoma
  • the method inhibits cancer cell invasion or migration in a subject having a high risk of cancer cell invasion or migration. In some embodiments, the method suppresses metastatic progression of cancer. In some embodiments, the method suppresses metastatic colonization of cancer. In some embodiments, the method slows the spread of a migrating cancer in a subject having a high risk of the spread of the migrating cancer. In some embodiments, the method reduced the rate of tumor seeding of a cancer in a subject having a high risk of tumor seeding of a cancer. In some embodiments, the method reduces or treats metastatic nodule-forming of a cancer in a subject having a high risk of metastatic nodule-forming of a cancer.
  • the method reduces metastatic risk of a cancer in a subject having a high metastatic risk. In some embodiments, the method treats metastatic cancer in a subject having a high metastatic risk. In some embodiments, the method reduces tumor heterogeneity.
  • the term “differentiation dose regimen,” refers to a dosing regimen (i.e. , a dosing level and frequency) of FHD 286, or a pharmaceutically acceptable salt thereof, that (a) increases the appearance of a marker of differentiation in one or more dedifferentiated cells of the cancer, (b) decreases the appearance of a marker of dedifferentiation in one or more dedifferentiated cells of the cancer, (c) induces cell arrest in one or more dedifferentiated cells of the cancer, or (d) induces apoptosis in in one or more dedifferentiated cells of the cancer.
  • a dosing regimen i.e. , a dosing level and frequency of FHD 286, or a pharmaceutically acceptable salt thereof, that (a) increases the appearance of a marker of differentiation in one or more dedifferentiated cells of the cancer, (b) decreases the appearance of a marker of dedifferentiation in one or more dedifferentiated cells of the cancer, (c) induces cell arrest in one or more dedifferent
  • hematologic cancer refers to cancers that begin in blood-forming tissue, such as the bone marrow, or in the cells of the immune system, e.g., leukemias, lymphomas, and myelomas.
  • Leukemias are cancers found in blood and bone marrow which are caused by rapid production of abnormal white blood cells.
  • Lymphomas are cancers which affect the lymphatic system.
  • Myelomas are cancers of the plasma cells.
  • Hematologic cancers normal blood cell development is interrupted by uncontrolled growth of an abnormal type of blood cell. The abnormal blood cells prevent the blood from performing many of its functions.
  • Hematologic cancers account for about 10% of all new cancer diagnoses. The 5-year relative survival rates for hematologic cancers range from about 50% to about 90%.
  • solid tumor refers to any cancer of body tissues other than blood, bone marrow, or the lymphatic system. Solid tumors can be further divided into those of epithelial cell origin and those of non-epithelial cell origin. Examples of epithelial cell solid tumors include tumors of the bladder, gastrointestinal tract, colon, breast, prostate, lung, kidney, liver, pancreas, ovary, head and neck, oral cavity, stomach, duodenum, small intestine, large intestine, anus, gall bladder, labium, nasopharynx, skin, uterus, male genital organ, urinary organs, and skin. Solid tumors of non-epithelial origin include sarcomas, brain tumors, and bone tumors.
  • dedifferentiation refers to the process by which a cell returns to a less differentiated (less specialized) stage in the cell lineage.
  • the lineage of a cell defines the inheritance of the cell (i.e., which cell came from where and which cells can form).
  • the cell lineage is the arrangement of cells within the genetic system of development and differentiation.
  • Lineage-specific markers refer to characteristics that are specific to the cell phenotype of the genealogy of interest and can be used to assess the differentiation of unassociated cells into the genealogy of interest.
  • dedifferentiated cells refer to cells that have returned to a less specialized position within the lineage of the cell.
  • the term “marker of differentiation” refers to refers to gene expression, physiology, function within the organism, proliferative activity, or morphology of a cell that demonstrates a more specialized or later state of the cell.
  • the markers of differentiation may be CD19, CD24, CD38, CD87, CD133, CD166, CD90, EpCAM, ALDH, Nanog, and Oct-3/4.
  • the markers for differentiation are CD11 b Gr-1 , CD33, CD123, CL-L-1 , TIM3, ALDH, Nanog, Oct-3/4, and Sox2.
  • Non-metastatic cell migration cancer refers to cancers that do not migrate via the lymphatic system or via haematogenous spread.
  • a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition.
  • the treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap.
  • the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated.
  • the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen.
  • composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human.
  • a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • a “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration.
  • the term “proliferation” as used in this application involves reproduction or multiplication of similar forms (cells) due to constituting (cellular) elements.
  • the combination therapies of the invention can decrease proliferation of cancer cells.
  • the terms “treat,” “treated,” or “treating” mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease.
  • Fig. 3 shows a series of graphs depicting the cells with CD11 b+/-, BRG1 +/-, and/or Ki67+/- markers in the population on Day 10 as described in Example 1 .
  • This invention is based in, at least in part, on the discovery that the dedifferentiated cell population, a subgroup of cancer cells, is responsible for the chemoresistance and cancer relapse, as it has ability to self-renew and to differentiate into the heterogeneous lineages of cancer cells in response to chemotherapeutic agents.
  • Dedifferentiated cells are also able to induce cell cycle arrest (quiescent state) that support their ability to become resistant to chemo- and radiotherapy.
  • Common chemotherapeutic agents target the proliferating cells to lead their apoptosis, as mentioned previously.
  • the methods of the invention provide a method for treating the dedifferentiated cells of a cancer to address a limitation of many anti-cancer therapies.
  • the differentiation dose regimen is typically an initial dose regimen (i.e., in a subject that is treatment naive or has not received a dose of FHD 286 for a period of at least 30 days) that comprises a higher dose than subsequent doses.
  • the differentiation dose regimen is a dosing regimen (i.e.
  • heterogeneity is one of the hallmarks of cancers arising in several organs. Genetic heterogeneity in the majority of the cancers is reflected by genome instability, and in addition to these genetic alterations, the state of the cell may be changed epigenetically. Phenotypic heterogeneity refers to the diverse functional properties and expression of different lineage markers that tumor cells can adopt along cancer progression. Based on cell surface markers, it is possible to identify distinct subpopulations of neoplastic cells within the same tumors, suggesting that irrespective of their genetic alterations, cancer cells exist in different states of differentiation (see, e.g., Visvader et al., Cancer stem cells: current status and evolving complexities.
  • intratumor heterogeneity refers to the molecular differences that occur between tumors initiated in the same organ, which allows the classification of these tumors in different subtypes, and which may (in some circumstances) represent biologically distinct disease entities (see, e.g., Visvader JE Cells of origin in cancer. Nature 469: 314-322 (2011)).
  • Glioblastoma the most common and aggressive subtype of the malignant gliomas, is characterized by intense proliferation, invasion, and intratumor heterogeneity. It has previously been demonstrated that the combined loss of p16 INK4a and p19 ARF enables mature astrocyte dedifferentiation in response to EGFR activation (see, e.g., Bachoo et al., Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1 : 269-277 (2002)).
  • Glioblastoma tumors induced by oncogenic lentivirus either in neurons or in glia in the cortex initially express differentiation markers (e.g., Tuj1 and GFAP, respectively), but as tumor progresses, these markers decrease and stem/progenitor markers become predominantly expressed (like nestin and Sox2) (See, e.g., Friedmann- Morvinski et al., Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338: 1080-1084 (2012)).
  • differentiation markers e.g., Tuj1 and GFAP, respectively
  • stem/progenitor markers become predominantly expressed (like nestin and Sox2)
  • CSCs from non-CSCs has also been found in tumors formed from intestinal epithelial cells (IEC).
  • IEC intestinal epithelial cells
  • an oncogenic hit like Kras and the activation of NF- KB induces the stabilization of p-catenin and thereof the activation of the p-catenin/tcf transcription complex, leading to the conversion of non-stem IEC into IEC with stem cell properties (see, e.g., Schwitalla et al., Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152: 25-38 (2013)).
  • Both Kras and TNF-a-dependent NF-KB activation enhances p- catenin/Tcf-mediated transcriptional activity and induces dedifferentiation of non-stem IEC into tumorinitiating cells.
  • AML Acute myeloid leukemia
  • ANLL acute non- lymphocytic leukemia
  • AML is the most common acute leukemia affecting adults, and its incidence increases with age.
  • AML is a relatively rare disease (accounting for approximately 1 .2% of cancer deaths in the U.S.) its incidence is expected to increase as the population ages.
  • AML AML-induced myeloma .
  • leukemic cells which causes a drop in red blood cells, platelets and normal white blood cells.
  • These symptoms include fatigue, shortness of breath, easy bruising and bleeding, and increased risk of infection.
  • risk factors and chromosomal abnormalities have been identified, but the specific cause of AML is unclear at this time.
  • AML progresses rapidly and is typically fatal within weeks or months if left untreated.
  • the cell culture method, flow cytometry method and flow cytometry analysis methods are relevant to the examples below.
  • CD34+ cells were isolated from primary cell samples (Proteogenex; Inglewood, CA) using EasySep Human CD34 Positive Selection Kit II (STEMCELL Technologies [STEMCELL]; Vancouver, BC, Canada) per manufacturer protocol. The separation step was repeated a total of 4 times. The cells were resuspended in 1 mL of Stem Cell Medium and seeded at 0.5 x 1 o 6 cells/mL for immediate use in the 7- day differentiation assay.
  • the plate was blocked with 50 pL/well of Fc block diluted 1 :20 in FACS buffer for 15 minutes on ice in the dark. The Fc block was removed by centrifugation and then the plate was washed with FACS buffer as before. Cells were resuspended in 50 pL surface antibody cocktail diluted in FACS buffer and incubated for 30 minutes on ice in the dark. The antibody cocktail was removed by centrifugation and then the plate was washed with FACS buffer as before. Cells were resuspended in Fix/Perm at 200 pL/well and incubated for 30 minutes on ice in the dark. The Fix/Perm was removed by centrifugation, and the plate was washed as before with 200 pL/well Perm buffer.
  • Example 1 Cancer cell lines are treated with FHD 286
  • the maintenance dose of FHD 286, or a pharmaceutically acceptable salt thereof is administered orally with an average daily dose of between about 1 .5 mg to 7.5 mg QD to the subject for a period of at least one to twenty-eight days.

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Abstract

La présente divulgation concerne des schémas posologiques pour FHD 286 pour le traitement de la LAM et de cancers hématologiques associés. Les thérapies selon l'invention peuvent réduire les effets secondaires, améliorer les résultats et/ou réduire la charge de dosage sur le patient.
PCT/US2024/050660 2023-10-10 2024-10-10 Schéma posologique de différenciation et d'entretien pour fhd 286 (inhibiteur de brg1/brm) Pending WO2025080767A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12486262B2 (en) 2020-01-29 2025-12-02 Foghorn Therapeutics Inc. Compounds and uses thereof

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US20210077486A1 (en) * 2019-09-12 2021-03-18 Aurigene Discovery Technologies Limited Method for Treating Diseases Using SMARCA2/4 Degraders
WO2023009834A2 (fr) * 2021-07-29 2023-02-02 Foghorn Therapeutics Inc. Méthodes de traitement du cancer

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US20210077486A1 (en) * 2019-09-12 2021-03-18 Aurigene Discovery Technologies Limited Method for Treating Diseases Using SMARCA2/4 Degraders
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Title
COLLINS MIKE, THOMSEN ASTRID, GARTIN ASHLEY, SANDOVAL GABRIEL J., ADAM AMMAR, REILLY SARAH, DELESTRE LAURE, PENARD-LACRONIQUE VIRG: "Abstract 2122: The dual BRM/BRG1 (SMARCA2/4) inhibitor FHD-286 induces differentiation in preclinical models of AML", CANCER RESEARCH, vol. 83, no. 7_Supplement, 4 April 2023 (2023-04-04), US , pages 1 - 4, XP093304715, ISSN: 1538-7445, DOI: 10.1158/1538-7445.AM2023-2122 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12486262B2 (en) 2020-01-29 2025-12-02 Foghorn Therapeutics Inc. Compounds and uses thereof

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