A PHASE 2 STUDY OF THE LSD1 INHIBITOR IMG-7289 (BOMEDEMSTAT) FOR THE TREATMENT OF ADVANCED MYELOFIBROSIS
Author(s): ,
Harry Gill
Affiliations:
Haematology,Queen Mary Hospital,Hong Kong,China
,
Abdulraheem Yocoub
Affiliations:
Hematology,University of Kansas,Kansas City,United States
,
Kristen Pettit
Affiliations:
Rogel Cancer Center,University of Michigan,Ann Arbor,United States
,
Terrence Bradley
Affiliations:
Sylvester Comprehensive Cancer Center,University of Miami,Miami,United States
,
Aaron Gerds
Affiliations:
Taussig Cancer Institute,Cleveland Clinic,Cleveland, OH,United States
,
Maciej Tatarczuch
Affiliations:
School of Clincal Sciences,Monash University,Melbourne,Australia
,
Jake Shortt
Affiliations:
Haematology,Monash Health,Melbourne,Australia
,
Natasha Curtin
Affiliations:
Haematology,Monash Health,Melbourne,Australia
,
James Rossetti
Affiliations:
Hillman Cancer Center,University of Pittsburgh,Pittsburgh,United States
,
Kate Burbury
Affiliations:
Haematology,Peter MacCallum Cancer Centre,Melbourne,Australia
,
Adam Mead
Affiliations:
Weatherall Institute of Molecular Medicine ,Oxford University,Oxford,United Kingdom
,
Joachim Göthert
Affiliations:
West German Cancer Center,University Hospital Essen,Essen,Germany
,
Stephen Koschmieder
Affiliations:
Hematology,Aachen University,Aachen,Germany
,
Anna Halpern
Affiliations:
Department of Hematology,University of Washington,Seattle,United States
,
Amber Jones
Affiliations:
Hematology,Imago BioSciences,South San Francisco,United States
,
Jennifer Peppe
Affiliations:
Hematology,Imago BioSciences,South San Francisco,United States
,
Georges Natsoulis
Affiliations:
Genetics,Imago BioSciences,South San Francisco,United States
,
Willis Navarro
Affiliations:
Hematology,Imago BioSciences,South San Francisco,United States
,
William Stevenson
Affiliations:
Kolling Institute of Medical Research,Royal North Shore Hospital,Sydney,Australia
,
Joanne Ewing
Affiliations:
University Hospitals Birmingham,NHS Foundation Trust,Birmingham,United Kingdom
,
Ruben Mesa
Affiliations:
UT Health San Antonio Cancer Center,University of Texas Health Science Center,San Antonio,United States
,
Elisa Rumi
Affiliations:
Haematology,Fondazione IRCCS Policlinico San Matteo,Pavia,Italy
,
Nicola Vianetti
Affiliations:
Policlinico S.Orsola-Malpighi,Universitaria di Bologna,Bologna,Italy
,
Monia Marchetti
Affiliations:
Azienda Ospedaliera,SS Antonio e Biagio e Cesare Arrigo,Alessandria,Italy
,
Claire Harrison
Affiliations:
Department of Clinical Haematology,Guy's & St Thomas' NHS Foundation Trust,London,United Kingdom
,
Alessandro Vannucchi
Affiliations:
Center for Research and Innovation of Myeloproliferative Neoplasms,University of Florence,Florence,Italy
,
Justin Watts
Affiliations:
Sylvester Comprehensive Cancer Center,University of Miami,Miami,United States
,
David Ross
Affiliations:
Haematology,Royal Adelaide Hospital,Adelaide,Australia
,
Moshe Talpaz
Affiliations:
Rogel Cancer Center,University of Michigan,Ann Arbor,United States
Hugh Rienhoff
Affiliations:
Hematology,Imago BioSciences,South San Francisco, CA,United States
EHA Library. Gill H. 06/09/21; 324797; EP1074
Dr. Harry Gill
Dr. Harry Gill
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP1074

Type: E-Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background
Patients with myelofibrosis (MF) require treatment when the clinical benefits of JAK inhibitors are exhausted; there is a clear need for novel therapies. Lysine-specific demethylase-1 (LSD1) is an enzyme critical for malignant stem cells and the differentiation, e.g., LSD1 licenses maturation of megakaryocytes, a key cell in MF pathogenesis.  IMG-7289 (bomedemstat) is an orally active LSD1 inhibitor that in mouse models of MPNs reduced peripheral cell counts, splenomegaly, inflammatory cytokines, marrow fibrosis and, importantly, mutant cell burdens (Jutzi et al. 2018).

Aims
IMG-7289-CTP-102 is an ongoing, multi-national, open-label, 24-week Phase 2 study of IMG-7289 taken once daily in MF patients resistant to all approved therapies. Key objectives are safety, and reduction a in spleen volume (SVR) and total symptoms scores (TSS).  A platelet count ≥100k/μL is a key inclusion criterion. Bone marrow (BM) biopsies and imaging studies are read centrally. Dosing is individually tailored using platelet count as a biomarker targeting a platelet count of 50-100k/μL.

Methods
At the censoring date (15Feb2021), 62 patients had enrolled, 24 patients remain on study. The median duration of treatment is 98 days (14-567). Median age is 68 (35-88) with 50% males; 47% had PMF, 34%, PET-MF, 19%, PPV-MF.  All but 6 patients were previously treated with ruxolitinib; 47% had received up to 3 additional treatments. 33% were transfusion-dependent. 58% were IPSS high-risk, 42% intermediate risk-2. Of driver mutations, 66% were JAK2, 27% CALR, 6% MPL and one triple-negative.  Of a panel of 261 genes mutated in AML/MPN/MDS, 65% had ≥2 mutation, 46% had ≥1 HMR mutations, 94% were in ASXL1.

Results
Of all enrolled patients evaluable at 24 weeks for TSS (N=13), 85% recorded a reduction in TSS (mean change -31%; -81% to 21%) with 31% reporting >50% reduction. Of all patients evaluable for SVR after 24 weeks (N=19), 81% had a reduction in SV from baseline (mean SVR: -8%; -41% to +37%).  72% of evaluable patients (N=36) had stable or improved hemoglobin (>1 g/dL). 26% of evaluable patients had an improvement in fibrosis score by 1 grade while 43% were stable.  Elevated serum LDH improved or resolved in 88%.  

In 32 patients to date, mutant allele frequencies (MAF) in driver and HMR mutations were reduced in 42% and stable in 50%. All driver mutations showed sensitivity to bomedemstat; most ASXL1 clones were subject to purifying selection by treatment. When MAFs in driver mutations were stable or decreased, SV and/or TSS was stable (n=2) or improved (n= 17).  In subjects with excess blasts (N=12), 8 (67%) improved or resolved during therapy.  There has been no progression to AML at up to 550 days. There was no obvious relationship among mutations, final optimal dose or response rates.  Germline variants will be discussed.  CN-LOH remains a strong driver of mutant gene dosage.  


55 patients (89%) reported 1001 AEs of which 63 were SAEs. Eight SAEs, 6 Grade 3 and 2 Grade 2, each occurring once, were deemed related by Investigators to IMG-7289: painful splenomegaly, rectal hemorrhage, cardiac failure, headache, vertigo, gastrointestinal hemorrhage, anaemia and pyoderma gangrenosum. There have been no safety signals, DLTs, or deaths related to drug.

Conclusion
In this first clinical study of an LSD1 inhibitor in MF patients, IMG-7289 as monotherapy was well-tolerated, improved symptom burdens and reduced spleen volume without safety signals.  Additionally, improvements in fibrosis scores, anemia and MAF have been observed.

The study is active and is enrolling in the US, UK, EU and Hong Kong.

Keyword(s): Epigenetic, Myelofibrosis

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP1074

Type: E-Poster Presentation

Session title: Myeloproliferative neoplasms - Clinical

Background
Patients with myelofibrosis (MF) require treatment when the clinical benefits of JAK inhibitors are exhausted; there is a clear need for novel therapies. Lysine-specific demethylase-1 (LSD1) is an enzyme critical for malignant stem cells and the differentiation, e.g., LSD1 licenses maturation of megakaryocytes, a key cell in MF pathogenesis.  IMG-7289 (bomedemstat) is an orally active LSD1 inhibitor that in mouse models of MPNs reduced peripheral cell counts, splenomegaly, inflammatory cytokines, marrow fibrosis and, importantly, mutant cell burdens (Jutzi et al. 2018).

Aims
IMG-7289-CTP-102 is an ongoing, multi-national, open-label, 24-week Phase 2 study of IMG-7289 taken once daily in MF patients resistant to all approved therapies. Key objectives are safety, and reduction a in spleen volume (SVR) and total symptoms scores (TSS).  A platelet count ≥100k/μL is a key inclusion criterion. Bone marrow (BM) biopsies and imaging studies are read centrally. Dosing is individually tailored using platelet count as a biomarker targeting a platelet count of 50-100k/μL.

Methods
At the censoring date (15Feb2021), 62 patients had enrolled, 24 patients remain on study. The median duration of treatment is 98 days (14-567). Median age is 68 (35-88) with 50% males; 47% had PMF, 34%, PET-MF, 19%, PPV-MF.  All but 6 patients were previously treated with ruxolitinib; 47% had received up to 3 additional treatments. 33% were transfusion-dependent. 58% were IPSS high-risk, 42% intermediate risk-2. Of driver mutations, 66% were JAK2, 27% CALR, 6% MPL and one triple-negative.  Of a panel of 261 genes mutated in AML/MPN/MDS, 65% had ≥2 mutation, 46% had ≥1 HMR mutations, 94% were in ASXL1.

Results
Of all enrolled patients evaluable at 24 weeks for TSS (N=13), 85% recorded a reduction in TSS (mean change -31%; -81% to 21%) with 31% reporting >50% reduction. Of all patients evaluable for SVR after 24 weeks (N=19), 81% had a reduction in SV from baseline (mean SVR: -8%; -41% to +37%).  72% of evaluable patients (N=36) had stable or improved hemoglobin (>1 g/dL). 26% of evaluable patients had an improvement in fibrosis score by 1 grade while 43% were stable.  Elevated serum LDH improved or resolved in 88%.  

In 32 patients to date, mutant allele frequencies (MAF) in driver and HMR mutations were reduced in 42% and stable in 50%. All driver mutations showed sensitivity to bomedemstat; most ASXL1 clones were subject to purifying selection by treatment. When MAFs in driver mutations were stable or decreased, SV and/or TSS was stable (n=2) or improved (n= 17).  In subjects with excess blasts (N=12), 8 (67%) improved or resolved during therapy.  There has been no progression to AML at up to 550 days. There was no obvious relationship among mutations, final optimal dose or response rates.  Germline variants will be discussed.  CN-LOH remains a strong driver of mutant gene dosage.  


55 patients (89%) reported 1001 AEs of which 63 were SAEs. Eight SAEs, 6 Grade 3 and 2 Grade 2, each occurring once, were deemed related by Investigators to IMG-7289: painful splenomegaly, rectal hemorrhage, cardiac failure, headache, vertigo, gastrointestinal hemorrhage, anaemia and pyoderma gangrenosum. There have been no safety signals, DLTs, or deaths related to drug.

Conclusion
In this first clinical study of an LSD1 inhibitor in MF patients, IMG-7289 as monotherapy was well-tolerated, improved symptom burdens and reduced spleen volume without safety signals.  Additionally, improvements in fibrosis scores, anemia and MAF have been observed.

The study is active and is enrolling in the US, UK, EU and Hong Kong.

Keyword(s): Epigenetic, Myelofibrosis

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