Table 4 Update on LSD1 inhibitors

Tranylcypromine

A monoamine oxidase inhibitor used in clinic for the treatment of depression

It is as an irreversible and weak LSD1 inhibitor

It exerts irreversible inhibition of LSD1 through the formation of a covalent adduct with FAD cofactor of LSD1 [246,247,248]

Tranylcypromine restores sensitivity to all-trans retinoic acid in AML [249]

A study to determine the RP2D of tranylcypromine in combination with fixed-dose ATRA and AraC (cytarabine) was initiated on March 24, 2016. (Phase I/II)

The details of the clinical study are as follows:

N = 60 (Goal), currently enrolling

Treatment—TCP (20,40,60,80 mg) + ATRA g/m² + AraC 40 mg on days 1–10

Study results—not yet posted (NCT02717884)

Safety and efficacy of the combination of tranylcypromine (TCP) and all-trans retinoic acid (ATRA) was evaluated in a phase 1 study in patients with R/R AML and high-grade MDS [250]. The details of the clinical study are as follows:

N = 15 (8 AML, 7 MDS)

Treatment—ATRA 45 mg/m² TCP 20 mg/m² OI BID (MTD)

TAAEs—Grade 1 and 2 (majority)

Grade 3/4 AE (> 10%) includes fever, thrombocytopenia, anemia and lung infection. Best evaluable responses included 5 patients with prolonged SD > 3 (2 AML, 1 CMML, 2 MDS), 1 marrow CR (MDS) and 1 MLFS (AML)

Overall the combination was found to be endowed with clinical activity and demonstrated an acceptable safety profile [250] (NCT02261779)

Another study (open-label, dose escalation, phase 1 study) to evaluate the efficacy of the combination of TCPA and all-trans-retinoic acid in patients with AML and MDS was also initiated on October 23, 2014. (NCT02273102)

Status—active, not recruiting

ORY-1001

Developed by Oryzon Genomics

ORY-1001, a tranylcypromine derivative, binds covalently to FAD and is a potent, selective and irreversible inhibitor of LSD-1 (IC₅₀ = 18 nM) [251]

ORY-1001 was found to induce time and dose dependent accumulation of H3K4me2 at LSD1 target genes

It induced cell apoptosis of THP-1 cells and inhibits colony formation and cell proliferation of MV(4;11) (MLL-AF4) cells (EC50 < 1 nM)

Oral administration of ORY1001 (< 0.020 mg/kg daily) caused substantial reduction of tumor growth in MV (4;11) xenografts after oral administration of < 0.020

mg/kg daily

ORY-1001 is stable in hepatocytes, possesses excellent oral bioavailability, activity, and target exposure in vivo [252]

Synergistic efficacy attained against human AML blast progenitor cells (BPCs) was recently demonstrated via co-treatment with ORY-1001 and BET protein inhibitor OTX015 [253]

ORY-1001 exhibits synergism with ATRA, cytosine arabinoside, and quizartinib), selective epigenetic and targeted inhibitors (e.g., EPZ5676, SGC-0946, decitabine, azacitidine, SAHA, and ABT-737) in the in vitro studies (MV (4;11), MOLM13, and MOLT4 cell lines) and also led to growth suppression of AML xenograft model. [254, 255]

ORY-1001 was evaluated in a phase 1 study in patients with acute leukemia (EUDRACT 2013-002447-29) and the results demonstrated that ORY-1001 was well tolerated at the recommended dose and promoted the differentiation of blast cells (64% patients). [252]. The details of the study are mentioned below:

N = 27 (26 AML, 1 ALL)

Treatment: ORY-1001 140mcg/m2/day 5 days week for 28-day cycle

DLTs: TCP, lobar pneumonia, febrile neutropenia (in combination with grade 2 fatigue and grade 2 erythema

multiforme)

Efficacy: OR in 5 (35%, 5 of 14), PR in 3 and SD in 2 patients. 9/14 patients had blast differentiation

Overall the results of the phase I clinical investigation of ORY-1001 in AML demonstrates the potential of the LSD1 inhibitor to exert therapeutic benefit. Some hematological toxicities such as thrombocytopenia and neutropenia were observed. [255]

A phase 1 study of ORY-1001 (orally administered) in patients with relapsed, extensive stage disease SCLC (NCT02913443) has been completed but the results have not been presented in public domain

GSK2879552 (GSK)

An irreversible tranylcypromine based LSD1 inhibitor

Endowed with activity in AML and SCLC

GSK2879552 decreased the cell proliferation in 19 of 25 AML cell lines and decreased blast count formation in 4 of 5 primary AML bone marrow samples

A notable reduction in GFP + cells and prolonged OS in comparison to control treated mice was evidenced in mice transplanted with AML cells. Moreover, surface expression of CD11b and CD86 was also observed [256]

Clinical evaluation of GSK2879552 (Phase 1//II) as a single agent as well as in combination with azacitidine in patients with MDS was also terminated (NCT02929498)

A clinical investigation (Phase 1 dose escalation study) of a combination of GSK2879552 and ATRA in patients with R/R AML was terminated (NCT02177812)

Another Phase 1 trial to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamics in patients with SCLC was also terminated (NCT02034123)

INCB059872

Developed by Imago BioSciences

It is a tranylcypromine based LSD1 inhibitor endowed with remarkable antiproliferative effects towards AML, Ewing’s sarcoma, SCLC, and prostate cancer (preclinical tumor models) [257,258,259,260]

Reduced proliferation and induced differentiation in AML cell lines and human AML cells was evidenced with INCB059872 (in vitro treatment) [259]

INCB05982 induced differentiation of blasts, reduced blast count, normalized counts, and prolonged survival consistent with anti-leukemic effects in the MLL-AF9 AML mouse model. [259]

Revelations from a preclinical investigation indicates synergistic effects of INCB059872 with ATRA in non-APL AML l systems [261]

Evaluation of INCB-59872 to assess safety, tolerability and antitumor activity (open label phase 1b study) is currently recruiting participants with R/R Ewing sarcoma (NCT03514407 and EudraCT 2018–000,062-11)

A dose escalation/dose expansion study of INCB059872 aimed at establishing the safety as well as tolerability profile of INCB059872 in subjects with advanced malignancies (AML/MDS, SCLC, MF, Ewing sarcoma, and poorly differentiated neuroendocrine tumors) was started in May, 2016 (NCT02712905, status—recruiting)

A phase 1/2 study to evaluate the safety and tolerability of INCB059872 in combination with pembrolizumab and epacadostat in subjects with advanced or metastatic solid tumors (NCT02959437) was carried out. The results of the study have not been disclosed

Phase I/II ABNL-MARRO trial for MDS or myeloproliferative disorders (NCT04061421, status—Not yet recruiting

A safety and biological activity evaluation study of INCB059872 in patients with sickle cell disease was recently terminated on March 1,2019 and the reasons stated for the termination were business oriented (NCT03132324)

IMG-7289 (IMG)

Developed by Imago BioSciences

Tranylcypromine based irreversible lsd1 inhibitor

IMG-7289 has demonstrated potential to inhibit the inflammatory cytokines production

In a study, treatment with IMG-7289 led to impairment of self-renewal and proliferation of neoplastic stem cells and also exhibited disease-modifying ability in MF

Studies conducted in mouse models of myeloproliferative neoplasms indicates that IMG-7289 decreased the elevated cell counts, inflammatory cytokines, mutant allele frequencies, spleen size, marrow fibrosis. [243, 262]

The IND application of IMG-7289 was accepted in 2018 by FDA for conducting the clinical investigation in MF [263]

IMG-7289 is currently being evaluated in the below mentioned studies:

Phase 2b study of IMG-7289 in patients with MF,

status – currently recruiting (NCT03136185)

A Phase 2 investigation of IMG-7289 (oral

administration, once daily) patients with essential

thrombocythemia (NCT04081220), status – currently

recruiting

Clinical evaluation of IMG-7289 with or without ATRA in patients with AML and MDS is completed (Phase 1, NCT02842827). The results are as follows:

N = 45, IMG-7289 ± ATRA 45 mg/m2

RP2D of IMG-7289 = 0.25 mg/kg

Overall, IMG-7289 was well tolerated in the study

CC-90011

Developed by Celgene

Is the first reversible LSD1

inhibitor in clinical trials that has demonstrated efficacy in advanced solid tumors and R/R NHL,

particularly in patients with

neuroendocrine tumors

[264, 265]

A study to evaluate the safety and efficacy of CC-90011 in patients with R/R Solid tumors and Non-Hodgkin's lymphomas was initiated on August 23^rd, 2016, status – recruiting

A phase 2 study was recently initiated to test the safety, tolerability, and preliminary efficacy of CC-90011 in combination with approved anticancer in patients with advanced stage SCLC (NCT03850067), status – recruiting

Phenelzine

A non-selective and irreversible monoamine oxidase inhibitor, Phenelzine, belongs to the hydrazine class and is used in clinic as an antidepressant and anxiolytic

It is LSD1 mechanism based inactivator similar to tranylcypromine, however utilizes the hydrazine functionality to initiate the key steps (mechanism) unlike the cyclopropyl oxidation (evidenced with Tranylcypromine) [266]

Phenelzine sulfate is undergoing clinical evaluation with Abraxane (Protein bound chemotherapy—combines paclitaxel with albumin) (NCT03505528)

SP-2509 (SP)

It is a reversible, selective and allosteric inhibitor of LSD1 (IC₅₀ = 13 nM)

It is not active against MAO-A and B [267, 268]

The outcome of a study has revealed that SP-2509 could induce differentiation of AML cell lines and primary AML. In addition, overall survival was prolonged in AML mouse models [267]

A clinical analog of SP-2509, SP-2577 is currently undergoing phase 1 clinical investigations in R/R Ewing’s sarcoma (NCT03600649)