Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylas... more Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR. Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalo...
Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with a highe... more Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with a higher incidence in older people. Most elderly AML patients are unfit for intensive chemotherapy and their treatment remains a challenge. Remission and survival rates decrease with age, and there is rather limited treatment success with standard (chemo)therapy, leading to 5-year survival rates of 20% or lower. Recent combinations of hypomethylating agents with pro-apoptotic agents such as venetoclax, a Bcl-2 inhibitor, have shown improved therapeutic prospects in early phase clinical trials, which still need to be supported by data from ongoing phase III confirmatory trials. Lysine-specific demethylase 1 (LSD1) participates in malignant transformation in AML. Iadademstat is a differentiating drug that selectively inhibits LSD1 and has shown efficacy in preclinical models, both alone and in combination with other compounds including azacitidine and Bcl-2 inhibitors. A First-in-Man phase I stud...
Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly pat... more Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge. Lysine-specific histone demethylase 1 (LSD1) contributes to the malignant transformation event in AML. Iadademstat (iada) selectively inhibits LSD1 and has shown efficacy in preclinical models, including promoting differentiation in AML. Iada has been administered so far to +100 oncology patients in different clinical trials, showing good safety. With a favorable ADME profile and high bioactivity allowing low dosing regimens, a low DDI risk is anticipated, making iada suitable for different drug com...
ACS Pharmacology & Translational Science, 2021
Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role ... more Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein−protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.
A novel point mutation in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene was found in a Tur... more A novel point mutation in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene was found in a Turkish patient with homozygous 3-hydroxy-3-methylglutaric acidemia. Amplification by RT-PCR of the mRNA using six different pairs of oligonucleotides produced no differences in four of the fragments amplified with respect to the control, but generated two fragments of different size. One was representative Abbreviations: HMGCoA, 3-hydroxy-3-methylglutaryl coenzyme A; HL, HMGCoA lyase gene; RT-PCR, reverse transcription-pctlymcraxc. chain reaction.
BZatteZZa germanica Has Two HMG-CoA Synthase Genes BOTH ARE REGULATED IN THE OVARY DURING THE GON... more BZatteZZa germanica Has Two HMG-CoA Synthase Genes BOTH ARE REGULATED IN THE OVARY DURING THE GONADOTROPHIC CYCLE*
PURPOSE Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with prec... more PURPOSE Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). METHODS This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor. RESULTS Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were...
ETHERAL is a global, multicentre, 12‐month, randomized, Phase IIa safety study of vafidemstat in ... more ETHERAL is a global, multicentre, 12‐month, randomized, Phase IIa safety study of vafidemstat in mild to moderate AD. The study includes a 6‐month, placebo‐controlled, 3‐arm period followed by a 6‐month, 2‐arm active treatment period where participants remain blinded to dose. Vafidemstat is the first epigenetic compound to be studied in clinical trials in CNS disorders. The primary endpoint is safety though data on cognition, behaviour and function and extensive CSF biomarker data was collected at 0, 6 and 12 months. The CSF biomarkers include amyloid and tau and the pro‐inflammatory biomarker S100A9, which is one of the top ten upregulated genes in late onset AD. This paper presents the first unblinded analysis of the data at the end of the first 6‐month period for the EU cohort.
Background Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects c... more Background Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-inhuman trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo. Objectives The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials. Methods This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary outcomes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated. Results No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the exception of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function. Conclusions Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses.
Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylas... more Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR.Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalom...
La biotecnología en Estados Unidos se estructura alrededor de ciudades que aúnan una serie de car... more La biotecnología en Estados Unidos se estructura alrededor de ciudades que aúnan una serie de características que facilitan la formación de empresas biotecnológicas: cercanía a centros de investigación, facilidades burocráticas, y presencia de otras biotech. Si bien el sector biotecnológico español es joven en comparación con el americano, la innovación y buena calidad del sector sanitario en España, han hecho que sea capaz de crecer y que algunas empresas hayan podido empezar a instalarse en EE UU con éxito, como es el caso de AbilityPharma y Oryzon
Introduction: Acute Myeloid Leukemia (AML) is an elderly disease with a rising incidence in the p... more Introduction: Acute Myeloid Leukemia (AML) is an elderly disease with a rising incidence in the past decades. Probability to achieve complete remission and survival rates decrease with age with standard chemotherapy options leading to very poor outcomes with less than 20% 5-year overall survival rates. It has been shown that Lysine-specific demethylase 1 (LSD1) is a partner in some gene transformation in AML and helps sustain the oncogenic process. Iadademstat is a potent and selective LSD1 inhibitor that has shown to be effective in preclinical models, both alone and in combination with other compounds, including azacitidine (Aza). A Phase I FiM study in acute leukemia showed that iadademstat exhibits a good safety profile and preliminary anti-leukemic activity as monotherapy. Iadademstat in combination with Aza may thus offer an alternative option for such a population with limited therapeutic options. Methods: ALICE is a Phase IIa clinical trial to assess the safety, tolerability...
the top 25 RNA genes in our gene panel with significant difference in RNA gene expression the maj... more the top 25 RNA genes in our gene panel with significant difference in RNA gene expression the majority of these RNA genes were downregulated (n¼20) in LN metastases, having a wide range of functions including proliferation, growth and survival. In contrast, the upregulated top RNA genes (n¼5) have a major role in cell adhesion, lymphoid tissue development and inflammatory response. Conclusion: Our findings highlight the RNA gene discordance between primary tumors and corresponding LN metastases indicating a non-homogeneous nature of the tumor mass at different anatomical locations with potential therapeutic applications.
The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid ... more The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.
Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylas... more Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR. Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalo...
Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with a highe... more Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with a higher incidence in older people. Most elderly AML patients are unfit for intensive chemotherapy and their treatment remains a challenge. Remission and survival rates decrease with age, and there is rather limited treatment success with standard (chemo)therapy, leading to 5-year survival rates of 20% or lower. Recent combinations of hypomethylating agents with pro-apoptotic agents such as venetoclax, a Bcl-2 inhibitor, have shown improved therapeutic prospects in early phase clinical trials, which still need to be supported by data from ongoing phase III confirmatory trials. Lysine-specific demethylase 1 (LSD1) participates in malignant transformation in AML. Iadademstat is a differentiating drug that selectively inhibits LSD1 and has shown efficacy in preclinical models, both alone and in combination with other compounds including azacitidine and Bcl-2 inhibitors. A First-in-Man phase I stud...
Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly pat... more Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge. Lysine-specific histone demethylase 1 (LSD1) contributes to the malignant transformation event in AML. Iadademstat (iada) selectively inhibits LSD1 and has shown efficacy in preclinical models, including promoting differentiation in AML. Iada has been administered so far to +100 oncology patients in different clinical trials, showing good safety. With a favorable ADME profile and high bioactivity allowing low dosing regimens, a low DDI risk is anticipated, making iada suitable for different drug com...
ACS Pharmacology & Translational Science, 2021
Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role ... more Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein−protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.
A novel point mutation in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene was found in a Tur... more A novel point mutation in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene was found in a Turkish patient with homozygous 3-hydroxy-3-methylglutaric acidemia. Amplification by RT-PCR of the mRNA using six different pairs of oligonucleotides produced no differences in four of the fragments amplified with respect to the control, but generated two fragments of different size. One was representative Abbreviations: HMGCoA, 3-hydroxy-3-methylglutaryl coenzyme A; HL, HMGCoA lyase gene; RT-PCR, reverse transcription-pctlymcraxc. chain reaction.
BZatteZZa germanica Has Two HMG-CoA Synthase Genes BOTH ARE REGULATED IN THE OVARY DURING THE GON... more BZatteZZa germanica Has Two HMG-CoA Synthase Genes BOTH ARE REGULATED IN THE OVARY DURING THE GONADOTROPHIC CYCLE*
PURPOSE Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with prec... more PURPOSE Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). METHODS This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor. RESULTS Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were...
ETHERAL is a global, multicentre, 12‐month, randomized, Phase IIa safety study of vafidemstat in ... more ETHERAL is a global, multicentre, 12‐month, randomized, Phase IIa safety study of vafidemstat in mild to moderate AD. The study includes a 6‐month, placebo‐controlled, 3‐arm period followed by a 6‐month, 2‐arm active treatment period where participants remain blinded to dose. Vafidemstat is the first epigenetic compound to be studied in clinical trials in CNS disorders. The primary endpoint is safety though data on cognition, behaviour and function and extensive CSF biomarker data was collected at 0, 6 and 12 months. The CSF biomarkers include amyloid and tau and the pro‐inflammatory biomarker S100A9, which is one of the top ten upregulated genes in late onset AD. This paper presents the first unblinded analysis of the data at the end of the first 6‐month period for the EU cohort.
Background Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects c... more Background Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-inhuman trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo. Objectives The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials. Methods This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary outcomes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated. Results No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the exception of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function. Conclusions Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses.
Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylas... more Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR.Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalom...
La biotecnología en Estados Unidos se estructura alrededor de ciudades que aúnan una serie de car... more La biotecnología en Estados Unidos se estructura alrededor de ciudades que aúnan una serie de características que facilitan la formación de empresas biotecnológicas: cercanía a centros de investigación, facilidades burocráticas, y presencia de otras biotech. Si bien el sector biotecnológico español es joven en comparación con el americano, la innovación y buena calidad del sector sanitario en España, han hecho que sea capaz de crecer y que algunas empresas hayan podido empezar a instalarse en EE UU con éxito, como es el caso de AbilityPharma y Oryzon
Introduction: Acute Myeloid Leukemia (AML) is an elderly disease with a rising incidence in the p... more Introduction: Acute Myeloid Leukemia (AML) is an elderly disease with a rising incidence in the past decades. Probability to achieve complete remission and survival rates decrease with age with standard chemotherapy options leading to very poor outcomes with less than 20% 5-year overall survival rates. It has been shown that Lysine-specific demethylase 1 (LSD1) is a partner in some gene transformation in AML and helps sustain the oncogenic process. Iadademstat is a potent and selective LSD1 inhibitor that has shown to be effective in preclinical models, both alone and in combination with other compounds, including azacitidine (Aza). A Phase I FiM study in acute leukemia showed that iadademstat exhibits a good safety profile and preliminary anti-leukemic activity as monotherapy. Iadademstat in combination with Aza may thus offer an alternative option for such a population with limited therapeutic options. Methods: ALICE is a Phase IIa clinical trial to assess the safety, tolerability...
the top 25 RNA genes in our gene panel with significant difference in RNA gene expression the maj... more the top 25 RNA genes in our gene panel with significant difference in RNA gene expression the majority of these RNA genes were downregulated (n¼20) in LN metastases, having a wide range of functions including proliferation, growth and survival. In contrast, the upregulated top RNA genes (n¼5) have a major role in cell adhesion, lymphoid tissue development and inflammatory response. Conclusion: Our findings highlight the RNA gene discordance between primary tumors and corresponding LN metastases indicating a non-homogeneous nature of the tumor mass at different anatomical locations with potential therapeutic applications.
The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid ... more The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.
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