Hydrogen sulfide (H2S) has recently emerged as a critical small molecule playing a major role in normal physiology and pathophysiology.
Via the action of metabolic enzymes, it is naturally generated at nanomolar levels in the heart, liver, kidney, nervous system, lung, airway tissues, eyes, gastrointestinal tract, reproductive organs, skeletal muscle, pancreas, joints, connective tissue, cochlea and adipose tissues of all mammalian species.
A deficit in circulating hydrogen sulfide is thought to lead to increases in oxidative stress, leading to associated problems that can contribute to heart failure, among other health issues: Subjects with congestive heart failure, for example, have been shown to suffer from a deficit in circulating and cardiac hydrogen sulfide levels. Plasma sulfide levels are inversely related to the severity of congestive heart failure. Decreased plasma hydrogen sulfide levels are also seen in people with type 2 diabetes, or those affected by obesity or by many other pathological conditions.
On the other hand, emerging evidence supports the views that -at last in the cardiometabolic setting- H2S-based treatments are often capable not only of halting disease progression, but also of leading to reversal of damage to tissues and organs, and that this regenerative effect is related to the ability of H2S to stimulate the proliferation of stem (progenitor) cells.
There are in fact numerous therapeutic targets for hydrogen sulfide, including cancer, heart failure, organ transplant, peripheral artery disease, inflammatory bowel disease, Alzheimer’s disease, acute myocardial infarction (MI), stroke, atherosclerosis, hypertension, erectile dysfunction, metabolic syndrome, diabetes, and thrombosis.
Sulfagenix has performed extensive research aimed at synthesizing safe, highly bioavailable and efficacious H2S donors. Sodium polysuthionate (“SG1002”), Sulfagenix’s lead H2S prodrug, is an orally active hydrogen sulfide precursor making up for the deficits that have been shown to exist in the above-mentioned health issues and others.
In clinical trials, SG1002 has demonstrated the ability to safely restore H2S homeostasis. Highly potent, SG1002 is the only hydrogen sulfide prodrug that converts 100% into H2S, making it the most efficient H2S-generating therapeutic agent in clinical development.
It is also extremely safe, with a very high therapeutic index and very mild gastrointestinal side effects. And, being orally active, it promotes patient compliance and ensures slow H2S release and is effective independently of H2S-generating enzyme levels. Thus, Sulfagenix’s lead H2S prodrug is able to release H2S at a slow, sustained and bio-regulated rate and to increase sulfur levels in blood and tissues of all vital organs.
It is indefinitely stable, with a shelf life greater than two years, and versatile, thanks to its high effectiveness in the treatment of multiple pathologies related to inflammation, immune dysregulation, oxidative stress, electrophilic stress and endoplasmic reticulum stress.
Importantly, H2S experts extremely potent antioxidant effects, both directly (by scavenging free radicals) and indirectly - via the NRF2 transcription factor and activation of over 200 cytoprotective genes.
As the source of a key nature-occurring antioxidant, Sulfagenix’s SG1002 holds the key to unlocking the regenerating abilities of the human organism.
Sulfagenix Australia has recently completed a Phase I study in 15 healthy subjects (n = 7) and heart failure patients (n = 8). Administration of SG1002 resulted in increased H2S levels in healthy subjects. We also observed increased H2S levels in HF subjects following 400 mg SG1002. Nitrite, a metabolite of NO, was increased in both healthy and HF patients receiving 400 mg and 800 mg SG1002. HF subjects treated with SG1002 displayed stable drug levels over the course of the trial. SG1002 was safe and well tolerated at all doses in both healthy and HF subjects. These data suggest that SG1002 increases blood H2S levels and circulating NO bioavailability. The finding that SG1002 attenuates increases in BNP in HF patients suggests that this novel agent warrants further study in a larger clinical study.
Polhemus DJ, Li Z, Pattillo CB, Gojon G Sr, Gojon G Jr, Giordano T, Krum H., A Novel Hydrogen Sulfide Prodrug, SG1002, Promotes Hydrogen Sulfide and Nitric Oxide Bioavailability in Heart Failure Patients. Cardiovasc Ther. 2015 Aug;33(4):216-26.
Based on safety identified in the Phase I study and achieving reasonable blood levels of hydrogen sulfide, the optimal dose along with placebo, will be used for continued evaluation in a Phase II study. The Phase II study will include heart disease patients randomly assigned to the SG1002 or placebo. The study will be carried out to demonstrate safety of chronic (3 months) drug administration and the ability to overcome deficits found in heart disease patients, including deficits in hydrogen sulfide anin markers of oxidative stress or heart disease. In addition to validating endpoints in the Phase I study, the Phase II study will also evaluate functional outcomes including quality of life parameters in patients with heart failure.