Sickle Cell Disease

SCD is a destructive disease with lifelong complications and debilitating symptoms.

Sickle Cell Disease (SCD) is a genetic blood disorder affecting hemoglobin, a protein in red blood cells that carries oxygen from the lungs to the body’s tissues and returns carbon dioxide from the tissues back to the lungs. SCD varies substantially in presentation and clinical course.

SCD is caused by an inherited mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the beta globin chain. This causes the formation of HbS, an atypical form of hemoglobin that can cause red blood cells to change shape, or sickle. Most SCD is caused by having two copies of the HbS gene, but in some cases one HbS gene can cause the disease if it is combined with a another Hb gene mutation.

A Heterogenous Disease – Several Genotypes

There are several genotypes of SCD found globally with the following being most prevalent:

HbSS
Patients inherit two sickle cell genes (‘‘S’’); one from each parent. This is often referred to as ‘‘sickle cell anemia’’ and is usually the most severe form of SCD.

HbSC
Patients inherit a sickle cell gene (‘‘S’’) from one parent and an abnormal hemoglobin gene called ‘‘C’’ from the other parent. This is usually a milder form of the disease.

HbS/Beta thalassemia:
Patients inherit a sickle cell gene from one parent, and a gene for β thalassemia, another form of anemia, from the other parent. There are two types of beta thalassemia: ‘‘0’’ and ‘‘+’’. βthal0 is often a more severe form while βthal+ is a milder form.

SCD’s Devastating Impact

Lifelong symptoms

SCD causes lifelong symptoms and complications that generally begin within eight to ten weeks of birth.

Severe pain

Painful vaso-occlusive crises (VOCs), which are acute episodes of severe pain, are the most reported and recognized complication of SCD.

Daily symptoms

SCD patients experience many daily symptoms, including chronic pain, fatigue and shortness of breath.

Damage to entire body

Although VOC is the most reported and recognized complication, SCD affects the entire body. Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to organs, including the brain, kidneys, lungs, bones and cardiovascular system.

Kidney Disease + SCD

1/3 develop chronic kidney disease

In fact, nearly one-third of people with SCD will develop chronic kidney disease and some of these patients will develop end-stage renal disease, or ESRD.

increased death rate

The one-year death rate following an ESRD diagnosis was almost three times higher in people with ESRD due to SCD when compared with those with ESRD from other causes.

Shorter life expectancy

These cumulative effects lead to a shortened life expectancy with an average of 42 years for males and 48 years for females in the United States.

The Problem

Nitric oxide deficiency underlies pathophysiology of SCD

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Nitric oxide deficiency plays an important role in the pathophysiology that underlies the accumulated damage that accompanies SCD. It is helpful to first understand the cascade of events that lead to nitric oxide deficiency in SCD.

In SCD, the sickled red blood cells are fragile and rupture, releasing their contents (including hemoglobin and an enzyme called arginase) into the bloodstream. The released hemoglobin binds and removes nitric oxide from circulation, and the released arginase breaks down L-Arginine, an amino acid that plays a key role in the production of new nitric oxide. Therefore, both the amount of existing nitric oxide is reduced and the body’s ability to produce new nitric oxide is limited.

The resulting low nitric oxide levels leads to lower levels of sGC stimulation, resulting in reduced cGMP production. Lower cGMP is associated with increased vascular inflammation, cell adhesion, vasoconstriction, vaso-occlusion and inadequate blood supply to organs.

Our Solution

Investigational, oral, once-daily olinciguat is designed to amplify nitric oxide signaling

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Our investigational, once-daily product candidate, olinciguat, is designed to amplify nitric oxide signaling through stimulating sGC to produce higher cGMP levels. Higher cGMP levels should decrease vascular inflammation and cell adhesion, and improve nitric oxide-mediated vasodilation and local blood flow. Higher levels of cGMP may also increase production of fetal hemoglobin (HbF), which can reduce the proportion of sickled red blood cells. By these mechanisms, we believe olinciguat may improve the daily symptoms of SCD, including chronic pain and fatigue, as well as decrease anemia, reduce the frequency of painful crises and ultimately prolong life by preserving organ function.

We believe this multidimensional pharmacological approach to the treatment of SCD has the potential to address the multifactorial pathology of this disease.

STRONG-SCD Phase 2 Study

Following the completion of Phase 1 studies in healthy volunteers that demonstrated a well-tolerated dose range, dose-proportional pharmacokinetics and target engagement, we initiated our Phase 2 study in patients with SCD, the STRONG-SCD study. STRONG-SCD is a randomized, placebo-controlled study in patients evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of three dose levels of olinciguat compared with placebo when administered once daily for 12 weeks.

The STRONG-SCD study is ongoing and enrolling approximately 88 patients aged 16 to 70 years with HbSS, HbSC, HbSβ0-thalassemia, or HbSβ+-thalassemia and who have experienced one to 10 painful crises in the past year.

To learn more about the study, please visit the STRONG SCD website or the study listing on ClinicalTrials.gov.

Read about the SCD patient advisory committee we’ve formed that is helping shape our understanding of SCD’s impact on patients and caregivers and informing our clinical development program.

Dominique, Sickle Cell Disease Patient

Photo by Raimon Norris

SCD Facts & Figures

Most common hemoglobin disorder worldwide

Globally, affects an average of 300,000 children born annually

Affects approximately 100,000 patients in the US

Standard part of mandatory newborn screening in US

About one in every 365 African American births

About one in 16,300 Hispanic-American births

Most prevalent genetic disease in France and the UK

Frequency is steadily rising in many other countries in Northern, Central and Southern Europe

Average SCD patient is admitted to the hospital seven times per year

Average length of stay per visit is seven days

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