Heart failure (HF) classification consists of two primary forms of the disease: Heart Failure with Reduced Ejection Fraction (HFrEF) and Heart Failure with Preserved Ejection Fraction (HFpEF), which each represent approximately 50% of the overall HF patient population.
There are treatments available for patients with HFrEF, but clinical progression and death still occur. For HFpEF, there is not a single approved drug or device to date – half of all HF patients have no treatment option available to them.
Neuregulin-1, also known as NRG-1 or simply neuregulin, is a growth factor that has shown great promise as a treatment for heart failure.
In animal studies, neuregulin has been shown to improve heart function in a variety of different models of heart failure.
In clinical studies, the growth factor by itself showed the ability to improve ejection fraction in HFrEF patients by nearly 10% absolute improvement at higher doses – a statistically significant and clinically meaningful improvement.
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Vermeulen et al., ErbB2 signaling at the crossing between heart failure and cancer,
Basic Res Cardiol (2016) 111:60
However, NRG-1 by itself has a short half-life in circulation. This requires higher doses to be administered, which have shown signs of toxicity, or for administration over a prolonged period of time – 10 hours per day for 10 consecutive days in Phase III studies.
NRG-1 dosing has also been limited by gastrointestinal (GI) side-effects and a theoretical risk of stimulating cancer progression.
Researchers have shown the NRG-1 acts through two different pathways – HER3 and HER4. The HER3 pathway appears primarily responsible for the GI side-effects and the cancer risk, while the HER4 pathway appears primarily responsible for the regenerative effects in the heart.
There is a belief in the research community that selectively activating HER4 without activating HER3 could yield a wider therapeutic window and better clinical effects.
- NRG-1 fusion domain can stimulate HER3 and HER4
- Anti-HER3 antibody blocks HER3 signaling
- Overall effect is selective stimulation of HER4 with a favorable pharmacokinetic profile