Turning mirror-image oligonucleotides into drugs: the evolution of Spiegelmer® therapeutics

•Aptamers are oligonucleotides that bind targets conceptually similar to antibodies.•Spiegelmers are plasma-stable, nonimmunogenic, mirror-image (l-configured) aptamers.•Spiegelmers were identified against various pharmacologically relevant targets.•Three Spiegelmers are in Phase II studies for diabetic complications and cancer.•Phase IIa data show proof-of-concept for the first Spiegelmer drug emapticap pegol. Spiegelmers are synthetic target-binding oligonucleotides built from non-natural l-nucleotides. Like aptamers, Spiegelmers fold into distinct shapes that bind the targets with high affinity and selectivity. Furthermore, the mirror-image configuration confers plasma stability and immunological passivity. Various Spiegelmers against pharmacologically attractive targets were shown to be efficacious in animal models. Three Spiegelmer candidates: emapticap pegol (NOX-E36; anti-CCL2), olaptesed pegol (NOX-A12; anti-CXCL12) and lexaptepid pegol (NOX-H94; anti-hepcidin), underwent regulatory safety studies, demonstrated good safety profiles in healthy volunteers and were taken into Phase IIa studies in patients. Proof-of-concept for emapticap pegol has recently been demonstrated in diabetic nephropathy patients. Furthermore, promising interim Phase IIa data of olaptesed pegol and lexapteptid pegol also suggest efficacy in the respective patient populations.