ORLANDO, Fla.—Idera Pharmaceuticals Inc., a clinical-stage biopharmaceutical company developing toll-like receptor and RNA therapeutics for patients with cancer and rare diseases, has presented initial clinical data from its ongoing Phase 1/2 clinical trial for IMO-8400, a Toll-like receptor (TLR) 7, 8 and 9 antagonist, being evaluated for the treatment of patients with relapsed or refractory Waldenström’s macroglobulinemia (WM). These results provide evidence that IMO-8400 has clinical activity and is well tolerated. The results were presented during a poster session at the 57th Annual Meeting of the American Society of Hematology in Orlando, Fla.
“Our clinical trial in Waldenström’s macroglobulinemia represents the first step in our understanding of the potential role that TLR antagonism could play in B-cell malignancies, specifically in those harboring the MYD88-L265P oncogenic mutation which is highly prevalent in Waldenström’s macroglobulinemia,” stated Vincent Milano, Idera’s CEO. “We are pleased that the initial results from this ongoing trial met our objectives in determining safety and tolerability, as well as clinical activity of IMO-8400 in this patient population. We are further encouraged that the safety profile seen to date will enable us to expand this study to evaluate higher dosing levels of IMO-8400.”
The results reported by Idera Chief Medical Officer Dr. Joanna Horobin are from 15 evaluable patients with WM who had a history of relapse or failure to one or more prior therapies and who completed at least one cycle of therapy with IMO-8400. Patients enrolled in the multi-center, open-label, dose ranging clinical trial which evaluated three dose levels of IMO-8400 (06. mg/kg weekly, 1.2 mg/kg weekly and 1.2mg/kg twice a week) administration for a period of up to 24 weeks. The primary objectives of the study were to assess safety and tolerability, with secondary objectives of assessing clinical activity, pharmacokinetics and defining the optimal dose for further clinical evaluation. In addition to clinical treatment parameters, cytokine levels were analyzed as an exploratory endpoint in the trial.
IMO-8400 was generally well tolerated at all dose levels studied. The maximum tolerated dose of IMO-8400 has not yet been identified.
Across all dose cohorts, six of 15 patients (40 percent) with relapsed or refractory WM had an objective response. Three responders were refractory to their last treatment, including one patient who was refractory to ibrutinib.
In the highest dose cohort, 1.2 mg/kg twice a week, three of six patients (50 percent) had an objective response and two had stable disease. The median time to first response was ~10.5 weeks.
There was improvement in bone marrow findings, hemoglobin and disease symptoms.
An exploratory analysis showed a significant correlation between change in M-protein and a change in IL-10, with decreases in IL-10 being seen in responding patients.
In summary, Milano stressed in a follow-up teleconference, these data in patients with WM provide the first clinical evidence supporting inhibition of the TLR pathway as a potential therapeutic approach for B-cell malignancies characterized by the MYD88 L265P oncogenic mutation. Evaluation of higher IMO-8400 dose levels is planned.
Waldenström’s macroglobulinemia is a rare and slow-growing form of B-cell lymphoma, with approximately 1,000 to 1,500 new cases diagnosed in the United States each year. The median age at diagnosis is between 60 and 70 years of age, and symptoms include fatigue, night sweats, headaches, visual problems, pain and abnormal bleeding due to complications such as anemia, retinopathy and peripheral neuropathy. Approximately 90 percent of WM patients present with the MYD88 L265P oncogenic mutation.
TLRs are receptor proteins that play a central role in the innate immune system. In healthy individuals, TLRs recognize invading pathogens and endogenous molecules released from damaged or dysfunctional cells, and initiate signaling cascades that trigger an inflammatory response. Through these signaling cascades, TLRs are also involved in activating the adaptive immune system, in which B-cells play a critical role. Based on its proprietary chemistry-based discovery platform, Idera discovered and is developing IMO-8400, which has demonstrated activity in multiple preclinical models of cancer and autoimmune disease.
Idera’s proprietary technology involves using a TLR-targeting technology to design synthetic oligonucleotide-based drug candidates that act by modulating the activity of specific TLRs. In addition to its TLR programs, the company is developing a third-generation antisense technology platform that it has created using its proprietary technology to inhibit the production of disease-associated proteins by targeting RNA.