A PHASE 2A STUDY OF THE LSD1 INHIBITOR IMG-7289 FOR THE TREATMENT OF MYELOFIBROSIS
Author(s): ,
Kristen Pettit
Affiliations:
University of Michigan,Ann Arbor,United States
,
Natasha Curtin
Affiliations:
Monash Health,Melbourne,Australia
,
Maciej Tartaczuch
Affiliations:
Monash University,Melbourne,Australia
,
Jake Shortt
Affiliations:
School of Clinical Sciences at Monash Health,Monash University,Melbourne,Australia
,
Justin Watts
Affiliations:
University of Miami, Sylvester Comprehensive Cancer Center,Miami,United States
,
William Stevenson
Affiliations:
Royal North Shore Hospital,Sydney,Australia
,
Aaron Gerds
Affiliations:
Cleveland Clinic Taussig Cancer Institute,Cleveland,United States
,
Kate Burbury
Affiliations:
Peter MacCallum Cancer Centre, University of Melbourne,Melbourne,Australia
,
Abdulraheem Yacoub
Affiliations:
University of Kansas,Kansas City,United States
,
Amber Jones
Affiliations:
Imago BioSciences,San Carlos,United States
,
Jennifer Peppe
Affiliations:
Imago BioSciences,San Carlos,United States
,
David M. Ross
Affiliations:
Royal Adelaide Hospital,Adelaide,Australia
Hugh Young Rienhoff, Jr.
Affiliations:
Imago BioSciences,San Carlos,United States
EHA Library. Pettit K. Jun 15, 2019; 267415; S832
Kristen Pettit
Kristen Pettit
Contributions
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Abstract

Abstract: S832

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 12:30 - 12:45

Location: Elicium 2

Background
Myeloproliferative neoplasms share a common pathophysiology of constitutive activation of the JAK/STAT pathway. Ruxolitinib, the only approved agent for the treatment for myelofibrosis (MF), can reduce spleen volume and symptom scores, but is not curative; disease will progress underscoring the need for therapies with a mode of action distinct from JAK inhibition.

IMG-7289 is an inhibitor of a lysine-specific demethylase, LSD1, an epigenetic regulator critical for self-renewal of malignant myeloid cells and differentiation of myeloid progenitors.  LSD1 bound to GFI1b licenses the maturation of progenitors to megakaryocytes and enables their normal function.  In mouse models of MPN (MplW515L, JAK2V617F), LSD1 inhibition reduced elevated peripheral cell counts, spleen volumes, inflammatory cytokines, mutant allele frequencies, and marrow fibrosis (Jutzi et al. 2018) supporting clinical investigation.

Aims
This multi-center, open-label Phase 1/2a study evaluated the safety, tolerability, steady-state pharmacokinetics and pharmacodynamics of IMG-7289 administered orally once-daily in adult patients with high- or intermediate-2 risk MF who were resistant to or intolerant of approved therapy. 

Methods
The primary objectives were safety, PK and spleen volume reduction.  Exploratory endpoints included reductions in total symptoms scores (TSS) using the MPN-SAF instrument and bone marrow (BM) fibrosis. Key inclusion criteria included platelet count ≥100K/μL and circulating blasts ≤10%.  Patients were treated daily for 12 weeks followed by a washout period of up to 28 days.  BM biopsies and imaging studies were conducted prior to treatment and after the 12 week dosing cycle.  The MPN-SAF was self-administered weekly.  Patients for whom clinical benefit was demonstrable could resume treatment for additional 12 week cycles.  Dosing was tailored using thrombocytopenia as a biomarker of megakaryocyte activity.  All patients were started at the presumed sub-therapeutic dose of 0.25 mg/kg/d and up-titrated weekly until the platelet count rested between 50 and 100K/μL.

Results
This preliminary analysis includes an enrolled cohort of 16 patients.  All but one patient had received one or more prior treatments including ruxolitinib.  44% had PMF, 38% PET-MF, 18% PPV-MF.  The median patient age was 65 (48-89) with 63% males. 56% were classified as high risk, the remainder, intermediate risk-2.  All patients were up-titrated from the starting dose; 75% were able to sustain a platelet count within the target zone with an average dose of 0.81 mg/kg.  88% (14/16) completed the 85 day study; eight remain on-study.  Two patients withdrew, one for fatigue (Day 33), one for accelerating disease (Day 39).  In evaluable patients (N=9), 66% demonstrated a reduction in spleen volume by imaging; 56% recorded a ≥50% reduction in TSS.  Two had an improved BM fibrosis score.  There were 239 AEs in 87% of the patients of which 15 were SAEs.  Of the SAEs, only one, painful splenomegaly, was deemed related to IMG-7289.  There have been no safety signals, DLTs, or deaths.  The median duration of treatment stands at 156 days (33-498) in this ongoing study.

Conclusion
This is the first report of the clinical use of an LSD1 inhibitor for MPNs.  IMG-7289 was well-tolerated in a heterogeneous population of patients with MF and limited therapeutic options.  IMG-7289 was effective in reducing spleen volumes and substantially improved symptom scores in a majority of patients.  On the basis of these results, this study has expanded into a Phase 2b trial to include EU and UK sites now open for enrollment.        

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Epigenetic, Myelofibrosis

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