Cyclerion fails sickle cell test, prompting pivot to CNS disease

Cyclerion CEO Peter Hecht (Business Wire)

Cyclerion Therapeutics has stopped development of olinciguat in sickle cell disease after getting a look at data from a phase 2 trial. The setback prompted Cyclerion to switch its focus to IW-6463 and the treatment of diseases of the central nervous system.

Ironwood Pharmaceuticals spinout Cyclerion took olinciguat into phase 2 in sickle cell disease on the strength of evidence it amplifies nitric oxide signaling. By amplifying signaling, Cyclerion predicted olinciguat would cut the proportion of sickled cells while simultaneously improving blood flow and endothelial integrity, thereby alleviating pain, fatigue and other sickle cell symptoms.    

The vascular sGC stimulator failed to live up to that promise. Cyclerion is yet to share data from the 70-subject phase 2 that compared four doses of olinciguat to placebo, stating only that the “results did not demonstrate adequate activity to support further internal clinical development.”

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In a statement, CEO Peter Hecht said Cyclerion is continuing to analyze the data to understand some potential biomarker signals, including inflammation, and exploring partnership options for the drug. Cyclerion’s internal focus is already moving away from olinciguat, though.

Cyclerion disclosed the setback at the same time as releasing data from a phase 1 clinical trial of CNS-penetrant sGC stimulator IW-6463. With olinciguat hitting the skids one year after praliciguat flunked a heart failure phase 2, Cyclerion is shifting its attention to IW-6463 and the treatment of CNS diseases.   

The data from the phase 1 trial of IW-6463 in healthy elderly subjects provide an early look at the merits of the switch to CNS diseases. Cyclerion terminated the trial when COVID-19 prevented some subjects from completing the second crossover period but still emerged from the study with results it framed as encouraging, including data related to attention and cognitive processing.

Buoyed by the data, Cyclerion is planning a multi-front clinical development strategy. Cyclerion is set to start enrolling 20 patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes soon. The single-arm phase 2a will assess the safety of IW-6463. Beyond that, Cyclerion is preparing to start a phase 2 clinical trial in Alzheimer’s disease with vascular pathology next year.

A lot is resting on IW-6463. Cyclerion spun off from Ironwood with two drugs in phase 2. Both drugs failed midphase trials, leaving IW-6463 as Cyclerion’s only other clinical-phase asset. 

Shares in Cyclerion fell more than 40% in premarket trading.

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