olinciguat (IW-1701) / Cyclerion - LARVOL DELTA

Study of IW-1701, A Stimulator of Soluble Guanylate Cyclase (sGC), in Patients With Type I or II Achalasia (clinicaltrials.gov) - P2a; N=9; Terminated; Sponsor: Cyclerion Therapeutics; Completed ➔ Terminated; The study was prematurely terminated due to enrollment challenges.

Clinical • Trial termination • Gastrointestinal Disorder • Rare Diseases

THE sGC STIMULATOR OLINCIGUAT ATTENUATES INFLAMMATION, VASO-OCCLUSION AND NEPHROPATHY IN MOUSE MODELS OF SICKLE CELL DISEASE. (PubMed, Br J Pharmacol) - "Our results suggest that the sGC stimulator olinciguat attenuates inflammation, vaso-occlusion, and kidney injury in mouse models of SCD and systemic inflammation."

Journal • Preclinical • Genetic Disorders • Hematological Disorders • Immunology • Inflammation • Renal Disease • Sickle Cell Disease • CST3 • LCN2 • OGA • sGC HDA+ • TNFA

Soluble guanylate cyclase stimulators and their potential use: a patent review. (PubMed, Expert Opin Ther Pat) - "After the first generation of sGC stimulators like riociguat or lificiguat, new compound classes with different physicochemical and kinetic profiles were identified, like the sGC stimulators vericiguat or praliciguat...Expert Opinion: With the recent advancements reported in the patent literature, sGC stimulators might be differentiated due to tissue selectivity or route of application although exhibiting the same molecular mode of action. The indication space of these compounds is potentially very broad and multiple indications in cardiovascular diseases and beyond are under investigation."

Journal • Review • Cardiovascular • sGC HDA+

[VIRTUAL] Olinciguat Protects Renal Function and Podocytes in In Vivo and In Vitro Models of Podocytopathies (KIDNEY WEEK 2020) - "In the genetic MRL/MpJ-Faslpr/J mouse model of systemic lupus erythematosus (SLE), disease progression, assessed by increased proteinuria, was less pronounced in mice treated with the positive control cyclophosphamide or with olinciguat than in vehicle-treated mice. In summary, olinciguat, an orally bioavailable sGC stimulator, exhibits significant reno-protective effects in nonclinical models and warrants further evaluation for the treatment of FSGS, other podocytopathies, or nephropathies associated with diseases such as sickle cell disease. Funding: Commercial Support"

Preclinical • Focal Segmental Glomerulosclerosis • Genetic Disorders • Glomerulonephritis • Hematological Disorders • Immunology • Inflammatory Arthritis • Leukopenia • Lupus • Nephrology • Renal Disease • Sickle Cell Disease • Systemic Lupus Erythematosus • sGC HDA+

Cyclerion Suspends Development of Olinciguat for Sickle Cell Disease (Sickle Cell Anemia News) - "Cyclerion Therapeutics has decided to suspend the development of olinciguat, its investigational oral therapy for sickle cell disease (SCD), after the treatment failed to show adequate activity in a Phase 2 clinical trial, the company announced....Top-line data revealed olinciguat was well-tolerated across all doses tested, but the therapy’s activity does not support further investigation, the company said. Cyclerion now plans to finish analyzing data from STRONG-SCD and present or publish results in a few months."

Discontinued • Sickle Cell Disease

STRONG-SCD: A Study of the Effect of IW-1701 (Olinciguat), a Stimulator of Soluble Guanylate Cyclase (sGC), on Patients With Sickle Cell Disease (SCD) (clinicaltrials.gov) - P2; N=70; Completed; Sponsor: Cyclerion Therapeutics; Active, not recruiting ➔ Completed

Clinical • Trial completion • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Cyclerion Announces Phase 2 STRONG-SCD Study Results in Patients with Sickle Cell Disease (GlobeNewswire) - "Cyclerion...announced top-line results from its STRONG-SCD study of olinciguat, an investigational, orally-administered, once daily, vascular sGC stimulator for the potential treatment of sickle cell disease (SCD). Olinciguat was generally well tolerated across all dose ranges. Results did not demonstrate adequate activity to support further internal clinical development. Cyclerion intends to complete its analysis of the study results and present or publish them in a future forum."

P3 data • Sickle Cell Disease

Cyclerion Therapeutics Reports Second Quarter 2020 Financial Results and Recent Corporate Highlights (GlobeNewswire) - "Olinciguat Program Update: Cyclerion has completed the treatment period in its STRONG-SCD study of olinciguat, an investigational, orally-administered, once-daily, vascular sGC stimulator, in Sickle Cell Disease (SCD) with a total of 70 patients randomized. STRONG-SCD is a randomized, placebo-controlled, dose-ranging study designed to evaluate safety, tolerability, and pharmacokinetics, as well as to explore effects on daily symptoms and biomarkers of disease activity when dosed over a 12-week treatment period. Top-line study results are expected in late Q3 2020."

P2 data • Trial status • Sickle Cell Disease

Cyclerion Therapeutics Completes $24 Million Private Placement (GlobeNewswire) - "...preparing for rapid further development of olinciguat in sickle cell disease should the upcoming Phase 2 data support that investment."

P2 data • Sickle Cell Disease

Study of IW-1701, A Stimulator of Soluble Guanylate Cyclase (sGC), in Patients With Type I or II Achalasia (clinicaltrials.gov) - P2a; N=20; Active, not recruiting; Sponsor: Ironwood Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting; Trial completion date: Jul 2018 ➔ Oct 2018; Trial primary completion date: Apr 2018 ➔ Sep 2018

Enrollment closed • Trial completion date • Trial primary completion date • Biosimilar

STRONG-SCD: A Study of the Effect of IW-1701 (Olinciguat), a Stimulator of Soluble Guanylate Cyclase (sGC), on Patients With Sickle Cell Disease (SCD) (clinicaltrials.gov) - P2; N=70; Active, not recruiting; Sponsor: Cyclerion Therapeutics; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Anemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease. (PubMed, Front Pharmacol) - "These antiproliferative effects were potentiated by the phosphodiesterase 5 inhibitor tadalafil, which did not inhibit vascular smooth muscle proliferation on its own. In a mouse TNFα-induced inflammation model, olinciguat treatment was associated with lower levels of endothelial and leukocyte-derived soluble adhesion molecules. The pharmacological features of olinciguat suggest that it may have broad therapeutic potential and that it may be suited for diseases that have both vascular and extravascular pathologies."

Journal • Preclinical • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Fibrosis • Heart Failure • Immunology • Metabolic Disorders • Renal Disease • sGC HDA+

Cyclerion Updates Corporate Progress (GlobeNewswire, Cyclerion Therapeutics, Inc.) - "Closed enrollment for olinciguat Phase 2 STRONG SCD study for sickle cell disease; topline data readout expected Q3 2020. Closed enrollment for IW-6463 translational pharmacology clinical study; topline data readout expected mid-year 2020. Company continues discussions to out-license praliciguat."

Clinical data • Commercial • Enrollment status • P2 data

Cyclerion to Present at the J.P. Morgan Healthcare Conference (GlobeNewswire, Cyclerion Therapeutics, Inc.) - "Management to review the Company's sGC clinical pipeline programs: praliciguat for diabetic nephropathy, olinciguat for sickle cell disease, and IW-6463 for neurodegenerative diseases."

Clinical

The Effect of the Soluble Guanylate Cyclase Stimulator Olinciguat on Renal Function and Biomarkers of Inflammation and Renal Injury in Sickle Cell Mice (ASH 2019) - "In summary, treatment of SCD mice with the sGC stimulator olinciguat elicited lower levels of plasma biomarkers of inflammation and endothelial cell activation and biomarkers of kidney injury."

CST3 • IL6 • KIM1 • sGC HDA+

Cyclerion Therapeutics and Collaborators to Present New Research on the Sickle Cell Disease Patient Journey at Upcoming Medical Meetings (GlobeNewswire, Cyclerion Therapeutics, Inc.) - "...Cyclerion will present preclinical data on its investigational sGC stimulator olinciguat and an overview of its Phase 2 STRONG SCD study."

Clinical • Preclinical

Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential. (PubMed, Nitric Oxide) - "Here, we give an overview of novel, orally available sGC stimulators that Ironwood Pharmaceuticals is developing. We outline the non-clinical and clinical studies, highlighting pharmacological and pharmacokinetic (PK) profiles, including pharmacodynamic (PD) effects, and efficacy in a variety of disease models."

Journal • Review

STRONG-SCD: A Study of the Effect of IW-1701 (Olinciguat), a Stimulator of Soluble Guanylate Cyclase (sGC), on Patients With Sickle Cell Disease (SCD) (clinicaltrials.gov) - P2; N=88; Recruiting; Sponsor: Cyclerion Therapeutics; Trial completion date: Jul 2019 ➔ Jul 2020; Trial primary completion date: Jul 2019 ➔ Jul 2020

Clinical • Trial completion date • Trial primary completion date

Cyclerion Therapeutics Reports Second Quarter 2019 Financial Results and Progress on Four Clinical Studies with Data Readouts Anticipated in the Next 12 Months (GlobeNewswire, Cyclerion Therapeutics, Inc.) - – Two praliciguat Phase 2 studies for diabetic nephropathy and heart failure with preserved ejection fraction (HFpEF) on track for data readouts in Q4 2019 – . – Phase 2 study of olinciguat in sickle cell disease on track for data readout in mid-2020 –. – Webcast investor event focused on praliciguat cardiometabolic programs to be held on September 17 in New York City ahead of anticipated clinical results – .

Clinical • Clinical data • Pipeline update

A Trial to Evaluate the Effect of Itraconazole (ITZ), a CYP3A4 Inhibitor, on the Pharmacokinetics of the Soluble Guanylate Cyclase Stimulator, Olinciguat (IW-1701), in Healthy Volunteers (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: Cyclerion Therapeutics; Active, not recruiting ➔ Completed

Clinical • Trial completion

THE SOLUBLE GUANYLATE CYCLASE STIMULATOR OLINCIGUAT ATTENUATES LEUKOCYTE/ENDOTHELIAL CELL INTERACTIONS IN BERKELEY SCD MICE (EHA 2019) - "Co-treatment of PDE9 inhibitors with hydroxyurea (HU) augments anti-inflammatory and anti-adhesive effects in these models (2, 3).Aims In response to NO binding, soluble guanylate cyclase (sGC) catalyzes synthesis of cGMP from GTP. Almeida CB., et al., Blood 2012 120(14):2879 3. Jasuja R., et al., Blood 2014 124(21):2694"

Preclinical

Cyclerion Therapeutics to Present Data on its Sickle Cell Disease Program at Upcoming Medical and Scientific Meetings (GlobeNewswire, Cyclerion Therapeutics, Inc.) - – In preclinical study, treatment with company’s investigational sGC stimulator olinciguat was associated with improved blood flow and reduced inflammation in a model of sickle cell disease – . The company will also present an overview of olinciguat, its sGC stimulator under clinical investigation in the Phase 2 STRONG SCD study as a potential treatment for sickle cell disease, at the 13th Annual Sickle Cell Disease Research and Educational Symposium, hosted by the Foundation for Sickle Cell Disease Research (FSCDR), and held June 7-9 in Fort Lauderdale, Florida.

Clinical data • Preclinical

A Trial to Evaluate the Effect of Itraconazole (ITZ), a CYP3A4 Inhibitor, on the Pharmacokinetics of the Soluble Guanylate Cyclase Stimulator, Olinciguat (IW-1701), in Healthy Volunteers (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: Cyclerion Therapeutics; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

Participants sought for trial evaluating olinciguat for sickle cell disease (Sickle Cell Anemia News) - P2, N=88; STRONG-SCD (NCT03285178); Sponsor: Cyclerion Therapeutics; "The trial’s main objective is to assess olinciguat’s safety and tolerability, along with the therapy’s pharmacokinetics (how the body processes the drug). Additional parameters include assessing the therapy’s effects on daily symptoms and biomarkers of disease activity....Top-line results from the STRONG-SCD trial are expected by mid 2020."

Clinical protocol • P2 data

Cyclerion Therapeutics Provides a Corporate and Pipeline Overview as a Newly Launched Public Biopharmaceutical Company (GlobeNewswire, Cyclerion Therapeutics, Inc.) - "Olinciguat, a once-daily, orally available vascular sGC stimulator in development for sickle cell disease (SCD): ongoing enrollment in the Phase 2 STRONG SCD study, and adding an additional (higher) dose. Topline data are expected in mid-2020."

Clinical data • Enrollment status