Do We Need Another HDAC Inhibitor in Multiple Myeloma?

Study of ACY-241 Alone and in Combination with Pomalidomide and Dexamethasone in Multiple Myeloma

NCT02400242

Acetylon Pharmaceuticals, Inc.

Six centers in the United States

60 patients, depending on number of dose levels

This is a phase I study evaluating the safety, maximum tolerated dose, and efficacy of the oral HDAC6 inhibitor ACY-241 as monotherapy and in combination with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (MM). Eligible patients include those who have received: 1) at least one line of prior therapy; 2) at least two cycles of lenalidomide; and 3) at least two cycles of a proteasome inhibitor (either as separate therapy or in the same line of treatment). ACY-241 is given orally daily on days one to 21 on a 28-day schedule for the first cycle, and subsequently in combination with pomalidomide and dexamethasone.

Histone deacetylase inhibitors (HDACi) such as vorinostat (Zolinza) and now panobinostat (Farydak) are an important new class of cancer therapeutics. By increasing histone acetylation, HDACi modulate the transcriptional profile of cells and other nuclear events. There are several classes of HDACi, and there are also nonhistone substrates of HDACi in the cytoplasm through which HDAC inhibitors exert manifold effects on protein degradation (via the aggresome), protein-protein interactions, and protein localization.

In MM, preclinical work targeting both proteasomal and aggresomal protein degradation systems with proteasome inhibitors and HDACi respectively, showed accumulation of polyubiquitinated proteins, followed by activation of apoptotic cascades and synergistic cytotoxicity (Pei XY et al. Clin Cancer Res. 2004;10:3839-3852; Richardson PG et al. Leuk Res. 2013;37:829-837; Santo L et al. Blood. 2012;119:2579-2589; Mishima Y et al. Br J Haematol. 2015;169:423-434). This motivated the clinical development of HDACi as part of MM combination therapy, beginning with vorinostat, a pan-HDACi. VANTAGE 088 was a phase III trial of vorinostat in combination with bortezomib, compared to bortezomib alone on a 21-day schedule in relapsed/refractory MM with one to three prior lines of therapy (Dimopoulos M et al. Lancet Oncol. 2013;14:1129-1140). While this study showed statistically significant improvement in progression-free survival (PFS), the difference was only 0.8 months and was not clinically meaningful.

Panobinostat (LBH589) is a newer oral pan-HDACI that was recently approved for the treatment of relapsed/refractory MM. PANORAMA1 was a phase III trial comparing panobinostat, bortezomib, and dexamethasone to bortezomib and dexamethasone in a similar patient population as VANTAGE 088 with one to three prior lines of therapy (San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206). This study enrolled 768 patients, and the median PFS was significantly longer in the panobinostat arm (11.99 months) versus the control arm (8.08 months; p<0.0001). The overall response rate (ORR) trended higher in the panobinostat arm, 60.7 percent versus 54.6 percent (p=0.09). However, similar to the VANTAGE 088 trial, there was more grade 3-4 diarrhea in the panobinostat arm (25%) than in the control arm (8%). Deaths due to other causes besides progressive disease were also higher in the panobinostat arm (7% vs. 3%). Given some of these concerns, the U.S. Food and Drug Administration (FDA) in November 2014 deferred accelerated approval of panobinostat as second-line therapy.

Panobinostat was re-evaluated earlier this year as third-line therapy. In a pre-specified subgroup analysis of 193 patients who received prior treatment with both bortezomib and an immunomodulatory drug, the improvement with panobinostat was significantly greater. The median PFS was 10.6 months in the panobinostat arm versus 5.8 months in the control arm, and the ORR was also higher: 59 percent versus 41 percent, respectively. Given the benefit in this more challenging-to-treat patient population, the FDA gave panobinostat accelerated approval in February 2015 in patients who have received at least two prior lines of therapy, including bortezomib and an immunomodulatory drug. However, the drug has a black-box warning of diarrhea, cardiac events, and arrhythmias. Some of the toxicity may reflect its inhibition across all HDAC classes.

Targeting of specific HDACs may be better tolerated than pan-HDAC inhibition. In particular, HDAC6 regulates acetylation of α-tubulin and the aggresome degradation pathway, and myeloma cells are vulnerable to HDAC6 inhibition (Hideshima T et al. Proc Natl Acad Sci U S A. 2005;102:8567-8572). Ricolinostat (ACY-1215) is an oral HDAC6-selective inhibitor that synergistically increases the apoptosis of myeloma cells when combined with lenalidomide or pomalidomide (Quayle SN et al. 2015. AACR Abstract 5380). In addition, this combination was found to further reduce expression of the transcription factors MYC and IRF4, which are implicated in myeloma progression. Ricolinostat is currently in phase I and II clinical trials in combination with bortezomib (NCT01323751), lenalidomide (NCT01583283), or pomalidomide (NCT01997840). Preliminary data from these trials show promising efficacy and an improved toxicity profile. ACY-241 has similar activity as ricolinostat against HDAC6, but has the advantage of availability as a tablet instead of ricolinostat’s liquid formulation. These findings set the stage for evaluating ACY-241 in combination with pomalidomide and dexamethasone.

Given that myeloma is a relapsing illness, patients need newer agents for their next line of therapy. The results of the PANORAMA1 study and the FDA approval of panobinostat are major advances for patients with MM. However, panobinostat is associated with significant toxicity, which likely reflects its activity across all HDAC classes. Selective inhibition of HDAC6 may be a means of enhancing the efficacy of HDAC inhibition, while improving tolerability. The trial of the oral HDAC6 inhibitor ACY-241 will test this therapeutic approach.