IMO-8400, an Antagonist of Toll-like Receptors 7, 8, and 9, in Development for Genetically Defined B-Cell Lymphomas: Safety and Activity in Phase 1 and Phase 2 Clinical Trials

Background. Toll-like receptors (TLRs) are pathogen-associated molecular pattern recognition receptors of the innate immune system. TLRs 7 and 9, which are expressed in human B-cells, respond to DNA- and RNA-based ligands by initiating a signaling cascade mediated through NF-κB, IRAK1/4, BTK, and JAK/STAT. DNA- and RNA-based ligands for TLRs 7 and 9 also are generated as damage-associated molecular patterns in certain autoimmune diseases and malignancies. MYD88 is a key adaptor molecule in TLR signaling. Recently, the oncogenic mutation MYD88 L265P mutation has been described and reported to occur in patients with activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), Waldenström’s macroglobulinemia (WM), and other B-cell malignancies. MYD88 L265P drives over-expression of TLR 7 and 9 signaling, creating an anti-apoptotic microenvironment that promotes cancer cell survival and proliferation. Recent epidemiological data confirm a strong association between the presence of MYD88 L265P and poor outcomes in patients with DLBCL. Specific targeting of signaling initiated by TLRs 7 and 9 therefore is a novel approach to the treatment of B-cell lymphomas harboring the MYD88 L265P mutation. Preclinical data presented at AACR 2014, including from xenograft tumor studies, show that IMO-8400 inhibits cell signaling and reduces tumor growth in WM and DLBCL models harboring the MYD88 L265P mutation. Clinical data from 2 completed trials of IMO-8400 are presented here.

Clinical Trial Designs. In a first-in-man Phase 1 trial in healthy subjects, IMO-8400 was administered by s.c. injection at single dosages of 0.1, 0.3, and 0.6 mg/kg and for four weeks at 0.3 and 0.6 mg/kg/week (each n=6). Goals of the Phase 1 trial included safety and tolerability evaluation through single- and multiple-dose escalation, and assessment of TLR engagement. Subsequently, a randomized, placebo-controlled Phase 2 trial was conducted with IMO-8400 in patients with moderate to severe plaque psoriasis at dosages of 0.075, 0.15, 0.3, and 0.6 mg/kg/week for 12 weeks (n=8 or 9 per dosage). Goals of the Phase 2 trial included safety and tolerability assessment over a 12-week treatment period, and evaluation of clinical proof of concept in a disease that involves TLR7 and 9 over-activation.

Clinical Trial Results. IMO-8400 was well tolerated across all dose regimens in both studies, with no treatment-related severe or serious adverse events, no drug-related treatment discontinuations, and no pattern of systemic adverse events or laboratory changes. The only treatment-related adverse events in more than one subject were injection site reactions, comprised of generally mild erythema with occasional induration, pruritus, tenderness or pain. In neither trial were there adverse or consistent shifts in laboratory parameters. Specifically, any changes in white or red blood cell parameters, platelet numbers, and liver enzymes or other serum chemistry parameters were similar following IMO-8400 treatment or after placebo treatment. In the Phase 2 trial, clinical proof of mechanism was demonstrated by increased frequency of improvements in psoriasis disease activity in IMO-8400-treated patients across multiple dose levels relative to placebo-treated patients.

Conclusion. Antagonism of TLRs 7 and 9 is a novel, scientifically-driven approach to the treatment of B-cell malignancies characterized by presence of the MYD88 L265P oncogenic mutation. IMO-8400, a clinical-stage drug candidate, was well tolerated in clinical trials conducted in healthy subjects and patients with psoriasis, having demonstrated no myelosuppression or any pattern of hematological or other toxicity in 12-week treatment regimens. The risk-benefit profile of IMO-8400 to date merits further clinical testing for genetically defined B-cell malignancies, as monotherapy and in combination with other agents. Based on the accumulated preclinical data, clinical safety, and demonstrated mechanism of action of IMO-8400, Phase 1/2 clinical trials of IMO-8400 are being conducted in both relapsed/refractory patients with WM and in patients with DLBCL and the MYD88 L265P mutation.