Immunoglobin G (IgG) antibodies play an important role in our body’s defense against viruses and bacteria, but they also contribute to autoimmune diseases. Working with investigators at Brigham and Women’s Hospital, scientists from Alexion Pharmaceuticals' recently acquired Syntimmune have shown that its FcRn inhibitor tackles the problem by taking a two-pronged approach.
With studies in mice, monkeys and humans, the team showed that FcRn blocker SYNT001 has the potential to treat autoimmune diseases by lowering not just IgG levels but also IgG circulating immune complexes (CICs). The findings are published in Science Advances.
Based on the positive results, Alexion last year shelled out $400 million upfront to acquire Syntimmune and the antibody drug, now called ALXN1830. The company plans to start a phase 2 study in warm autoimmune hemolytic anemia in early 2020, and, pending results from another phase 1, it will launch a phase 2 study of a subcutaneous form of the drug in generalized myasthenia gravis (gMG).
FcRn (neonatal Fc receptor) is considered a “protection” receptor that helps prevent the breakdown of IgG. Previous studies have shown that blocking FcRn can reduce the level of circulating IgG in humans. Richard Blumberg, M.D., and colleagues at Brigham previously demonstrated in mouse studies that FcRn also shields CICs, as when FcRn is missing from hematopoietic cells, CICs are cleared more quickly from circulation.
IgG can form immune complexes with the antigens. Because IgG CICs further contribute to several autoimmune disorders, Blumberg and teammates suggest that inhibiting FcRn might also dampen autoimmune response related to IgG CICs.
SYNT001 promoted clearance of both human IgG antibodies and IgG ICs in a mouse model, the team found. In a small phase 1a involving 31 healthy human individuals, the drug reduced the blood concentrations of IgG as expected. On top of that, SYNT001 led to a significant dose-dependent reduction of CIC in the participants, the investigators reported. The lowest CIC levels occurred seven days after a single shot of SYNT001, as reductions from baseline ranged from 18.98% to 48.39% across the dosage arms, and the effect persisted for at least a month.
When examining the results outside of the body, the researchers observed that blocking FcRn with SYNT001 also inhibited the ability of IgG ICs to induce production of inflammatory cytokines by while blood cells.
FcRn is a popular target that's been hotly pursued by several companies developing treatments for IgG-related autoimmune diseases. Alexion itself doubled down on the area in March with a deal to co-develop Affibody’s ABY-039. The drug is an antibody mimetic that’s much smaller than a typical antibody, a feature Alexion believes extends its half-life and can be delivered in low-volume via subcutaneous injection.
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Belgian biotech Argenx is currently a front-runner in the field, with its efgartigimod (ARGX-113) already in phase 3 trial in gMG patients with top-line results expected in the second half of 2020. It also has other mid- or late-stage trials planned or scheduled to read out soon in primary immune thrombocytopenia, pemphigus vulgaris and chronic inflammatory demyelinating polyneuropathy.
Other FcRn players include UCB’s rozanolixizumab, Momenta Pharmaceuticals’ nipocalimab (M281) and Roivant’s RVT-1401.
The ability to remove CICs with a drug could change the treatment paradigm, the Brigham-Syntimmune team noted in the new study.
“We anticipate that FcRn antibody therapeutics will be part of an important new class of drugs for the treatment of autoimmune diseases,” co-author Blumberg said in a statement. “As these types of drugs move into the clinic, we need to pay attention to their effects on IgG immune complexes as that is something which has not received the attention it deserves.”