MIS416 is an investigative therapy under development by Innate Immunotherapeutics to treat people with secondary progressive multiple sclerosis (SPMS). It is a naturally occurring agent derived from bacteria that can alter immune system responses. MIS416 is administered weekly via intravenous injection.
How MIS416 works
MIS416 is a construct that contains two naturally occurring ligands called TLR-9 and NOD-2. Ligands are molecules that can interact with specific receptors, triggering a signaling pathway. Both TLR-9 and NOD-2 are involved in pathogen recognition and the activation of the immune system.
TLR-9 and NOD-2 activate a series of signal transduction pathways that alter the action of the immune system. They act to stimulate a low-level production of inflammatory cytokines (a type of protein involved in triggering an immune response), which results in a negative feedback mechanism.
This reduces the activity of inflammatory T-cells, as shown using a mouse model of MS. (T-cells are a type of immune cell that can cause damage to the central nervous system of MS patients via inflammation).
These early preclinical studies suggested that MIS416 has the potential to treat MS in humans.
MIS416 in clinical trials
Innate Immunotherapeutics, based in Sydney, Australia and Auckland, New Zealand, completed a Phase 1/2 clinical trial (NCT01191996) in 2012.
This was a dose-escalating trial over 12 weeks in healthy participants and in progressive MS patients testing the drug candidate’s safety, tolerability, and effectiveness. The study also tested MIS416’s pharmacodynamics (how the body reacts to the drug) and pharmacokinetics (how the drug is processed in the body).
Results of the study, published in the scientific journal Multiple Sclerosis, showed the drug was well tolerated, identified a dosage for additional clinical studies, and led to an improvement in Expanded Disability Status Scale (EDSS) scores in half the study’s participants.
Following the early success of MIS416, the company progressed to a Phase 2b placebo-controlled trial involving 93 patients with secondary progressive MS (NCT02228213). This one-year study evaluated the effectiveness and safety of MIS416 in 62 SPMS patients who were randomly assigned to receive weekly injections of the investigational drug from the 93 trial subjects. The rest (31 of the 93 participants) received injections of an inactive placebo.
This study was conducted in Australia and New Zealand in collaboration with INC Research.
Unfortunately, no clinically meaningful or statistically significant difference in EDSS scores or changes in brain volume between patients treated with MIS416 or placebo were recorded. Researchers concluded in June 2017 that MIS416 appears to have no benefit as a therapy for SPMS.
Despite the Phase 2 setback, Innate Immunotherapeutics intends to continue studying MIS416 and analyzing the Phase 2 trial results to see if there are potential responders that weren’t immediately evident in the initial analysis.
The company spent eight years developing the drug, and provides it to a limited number of Australian MS patients under a compassionate use program. Innate’s CEO Simon Wilkinson described the results as a “shock” and “not what we were expecting based on our previous clinical experience with MIS416.”
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