SCIENCE

Pipeline

Elevian is moving forward several programs utilizing both rGDF11 and other modulators of the GDF11 pathway.

Stroke: An Area of Major Unmet Medical Need

Globally, stroke is an area of huge unmet medical need, and of the approximately 15 million people who suffer from strokes annually 33% die and another 33% are left permanently disabled. Worldwide, stroke is the leading cause of long-term disability and the second leading cause of death.

Disease Overview

Strokes occur when blood supply to a part of the brain is disrupted resulting in decreased oxygenation, subsequent the death of brain cells in the affected region and the loss of neurological function.  Ischemic and hemorrhagic stroke are the two major types of stroke.  Ischemic stroke is the most common type of stroke (87% in the US and is caused when blood vessels in the brain become narrowed or blocked, resulting in reduced blood flow to the affected brain region.  Risk factors for ischemic stroke include age, diabetes, cardiac disease, hypercholesterolemia, and obesity.  Hemorrhagic strokes occur when blood vessels in the brain leak or rupture.  The most common cause of hemorrhagic stroke is hypertension.

Current Treatments

Currently, approved therapies or surgical treatments for stroke are designed to protect the injured brain regions from further damage.  However, none of these “neuroprotective” approaches promote regeneration and recovery post stroke.  For ischemic stroke, the clot busting drug recombinant Tissue Plasminogen Activator (rtPA) is used to restore blood flow to the ischemic regions of the brain but must be given within 3 - 4.5 hours after the stroke.  A surgical endovascular approach called mechanical thrombectomy can be used up to 16 hours after a stroke, but is limited to large vessel occlusions.  Only ~20% of ischemic stroke patients receive neuroprotective treatments and half of those have ongoing deficits. 

Only supportive care is available for patients who suffer from a hemorrhagic stroke.  The primary goal for these patients is to provide basic life support, and control bleeding, intracranial pressure, blood pressure, and seizures.  Surgical intervention and endovascular therapy are employed to address the cerebellar hematoma, while antihypertensive and anti-seizure drugs are used to control pressure and seizures.

There are no approved treatments that promote recovery or regeneration in the hours and days after either ischemic or hemorrhagic stroke.

Elevian’s Therapeutic Approach to Stroke

Elevian is developing new medicines that promote regeneration and recovery.  Our goal is to transform the lives of patients and families dealing with debilitating degenerative neurologic diseases.  For stroke, our focus is to address the huge population of patients (approximately 10 million new patients per year worldwide) who become permanently disabled or die post stroke.  

rGDF11 Improves Recovery Post-Stroke

Elevian is advancing recombinant Growth Differentiation Factor 11 (rGDF11) to the clinic to improve neurological function after both ischemic and hemorrhagic stroke. GDF11 a circulating blood factor that has been demonstrated to stimulate regeneration broadly and consistently in multiple tissues and organs. In the brain, Dr. Lee Rubin, one of Elevian’s scientific co-founders, demonstrated that rGDF11 increases the density of blood vessels and the number of neural stem cells in the brain of aged mice (Katsimpardi et al, 2014; Ozek et al 2018). Elevian has confirmed those findings in the brains of aged mice. Because new blood vessel formation (neovascularization) and neurogenesis are reported to play an important role in regeneration and recovery post stroke (Hatakeyama et al, 2021; Rahman et al, 2021; and Esquiva et al, 2018), we evaluated the benefits of rGDF11 in validated rodent preclinical models of ischemic and hemorrhagic stroke.

Ischemic Stroke

In the rat permanent Middle Cerebral Artery Occlusion (pMCAO) model of ischemic stroke Elevian has shown that rGDF11 improves limb and core body motor function measures (forelimb placement, hindlimb placement, and elevated body swing) when dosing is initiated within 24 hours or up to several days post stroke. Data from other laboratories demonstrating benefits of rGDF11 in several rodent preclinical stroke models also demonstrate that rGDF11 improves motor function recovery post stroke (Ma et al, 2018; Lu et al, 2018; and Hudobenko et al. 2020).  rGDF11 was also shown to increase blood vessel density and neurogenesis in stroke models, demonstrating its regenerative potential in stroke models. The reproducibility of these data from Elevian and other laboratories are indicative of the potential for rGDF11 treatment to improve motor function recovery in patients when treatment is initiated either shortly after the stroke or several days later, if diagnosis and treatment is delayed.

Hemorrhagic Stroke

Elevian has also demonstrated that rGDF11 is efficacious in a mouse model of hemorrhagic stroke. In this study, rGDF11 improved sensory, vestibular-motor, and motor function, including gait speed and forelimb function.

GDF11 Promotes Recovery & Regeneration in Multiple Tissues and Organs

GDF11 has been demonstrated to promote recovery and regeneration broadly and consistently in multiple tissues and organs.  In addition to the effects on the brain, Elevian’s team and others have reported beneficial effects in animal models of aging and aging-related diseases, including cardiovascular, neurological, metabolic, pulmonary, renal, inflammatory, and skeletal muscle dysfunction.

Elevian has demonstrated that rGDF11 improves glucose metabolism, insulin response, insulin sensitivity, and promotes weight loss, in a diet-induced model of obesity and Type II Diabetes.  Additional efficacy and mechanistic preclinical studies are being performed as we advance rGDF11 for metabolic disease.

rGDF11 Effects in Preclinical Models of Diet-Induced Obesity & Diabetes

These data demonstrating broad beneficial effects of rGDF11 in multiple indications including stroke (ischemic and hemorrhagic), metabolic disease (obesity and type 2 diabetes), and cardiovascular disease are indicative that therapeutics targeting the GDF11 pathway have the potential to improve the health of patients presenting with these common co-morbidities.This is particularly important for the many people who suffer from stroke with metabolic and cardiovascular disease complications.

rGDF11 Protein Manufacturing

Elevian has developed a stable high producing rGDF11 cell line and a scalable purification process to produce high quality, active rGDF11.  Manufacturing activities to support IND Enabling safety and toxicology and early clinical studies are ongoing.

Intellectual Property

Elevian holds exclusive worldwide rights to a growing portfolio of patents from Elevian, Harvard, and affiliated research partners, including:

• Pharmaceutical composition comprising a GDF11 polypeptide;

• Use of GDF11 to treat stroke, obesity, Type II diabetes, and a number of aging-related diseases; and

• New compositions to modulate GDF11 activity.