In preclinical studies, LSD1 inhibitors derived from tranylcypromine were active in acute myeloid leukemia models, particularly in the MLL-translocated subtype. We now report the safety, PK and PD properties of ORY-1001 (a potent and selective inhibitor of LSD1) in a multicenter phase I study (EUDRACT nº 2013-002447-29).

The primary objective was to assess safety and tolerability in relapsed or refractory acute leukemia (RR-AL). Secondary objectives were to a) characterize PK, b) to monitor a panel of surrogate PD markers for target engagement and c) assess clinical response. Patients ≥16yr with RR-AL, ECOG PS ≤2 and life expectancy >8wk were eligible. ORY-1001 was administered orally once daily in a 28 day cycle (5d ON/2d OFF x4wk). Plasma ORY-1001 levels were analyzed by HPLC-MS/MS. Blood leukocyte expression of candidate differentiation PD biomarkers was determined by qRT-PCR.

Twenty-seven subjects (mean age 66.5, range 40-81; gender 19 M/8F) were recruited into the dose escalation phase (26 - RR-AML; 1 - RR-ALL). Mean time since initial diagnosis was 12.6 months and since last treatment was 2.1 months. Twenty patients completed cycle 1, 9 started cycle 2 with 3 completions and 3 started and completed cycle 3. The most frequent ADR was thrombocytopenia (7 events, 5 subjects). Twenty-two subjects experienced 32 SAEs of which two (Cohort 8 - 220 µg/m2/d) were considered possibly related to ORY-1001: grade 5 lobar pneumonia and grade 3 febrile neutropenia (in combination with grade 2 fatigue and grade 2 erythema multiforme). These were considered dose limiting toxicities. Consequently the recommended dose for the extension phase was established at 140 μg/m2/d. At the end of the dose escalation phase, 358 treatment emergent AEs were reported. The most frequent were asthenia (16 events, 12 subjects), febrile neutropenia (15 events, 13 subjects), constipation (12 events, 9 subjects) and peripheral oedema (11 events, 8 subjects).

ORY-1001 plasma concentration increased with dose across cohorts. At 140 µg/m2/d (recommended dose) on d1 mean±SD Cmax was 13.1±7.2 and mean±SD AUC (0-24h) was 181.7±61.3pg.hr/mL. On d5 mean±SD Cmax was 42.2±27 and mean±SD AUC (0-24h) 723.3±341.5pg.hr/mL.

PD biomarker response varied due to differences in disease genetics and circulating blast percentages. Nevertheless select biomarkers demonstrated time and dose dependent response profiles in individual patients. For example, PI16 (peptidase inhibitor 16; or CRISP-9) levels were induced in cohort 7 (140 µg/m2/d). Maximum PI16 induction was seen at 18hr on d1, pre-dose levels remained high on d5 and were sustained through the OFF period until pre-dose on d8.

An extension cohort of 14 patients (mean age 57; range 30-78, gender 8M/6F) with specific RR-AML subtypes predicted to be more sensitive based upon preclinical studies, was also enrolled (AML MLL-translocated n=10; acute erythroleukemia/M6 n=4). At data cut-off (31 July 2016), 131 AEs and 27 SAEs have been reported. Eight SAEs were considered related to treatment, including a differentiation syndrome in two patients. PK and PD analyses are ongoing. For response assessment, 14 patients were evaluable. Objective responses were seen in 5/14 patients (36%): two patients with t(9;11) exhibited stable disease and three a partial response (one MLL after 3 cycles, and two M6). Importantly, there was evidence of morphologic blast differentiation in blood and/or BM in 9/14 patients (5 MLL and 4 M6).

In summary, ORY-1001 at the recommended dose is well tolerated and promotes blast cell differentiation in 64% of patients. This, together with the partial responses observed, suggest that LSD1 inhibition may be a possible therapy for some AML patients.


Somervaille:Novartis: Consultancy, Honoraria; Imago Biosciences: Consultancy. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Molinero:Oryzon Genomics: Employment, Equity Ownership. Mascaro:Oryzon Genomics: Employment. Maes:Oryzon Genomics: Employment, Equity Ownership.

Author notes


Asterisk with author names denotes non-ASH members.