A Brief History of the Development of SG1002
The First Oral Hydrogen Sulfide Prodrug
Twenty-five years ago, Gabriel Gojón Romanillos had a brilliant insight that laid the groundwork for the creation of a company and a series of studies with milestones that include a clinical trial (phase I) in Australia. That insight allowed him to foresee the use of metal sulfides and hydrogen sulfide (H2S) as extremely potent reducing agents capable of exerting therapeutic effects on mammals affected by pathologies originating in oxidative stress.
At that time (ca. 1996) the mainstream scientific community held the belief that H2S was a highly toxic (and frequently lethal) gas absolutely devoid of any redeeming quality. In fact, although the first hint that H2S might possess other than pathophysiological roles was published in 1996 by Abe and Kimura, five more years were to elapse before the physiological importance of H2S was appreciated.
Gojón Romanillos had to relentlessly fight the establishment during several years, but his conviction, enthusiasm and tenacity eventually allowed him to convince others (including several MD) that his hypothesis was reasonable on evolutionary and biochemical grounds.
His pioneering studies initially involved the development of gastroprotected formulations of inorganic sulfide compounds such as sodium sulfide (2013) and their oral administration, first to himself and then to many terminal cancer patients, as well as to individuals affected by serious cardiovascular pathologies, always under medical supervision. The remarkable treatment success obtained in most cases — in spite of the fact that patients where ingesting an inorganic sulfide in doses far in excess of the lethal one — are documented in the 32 “Utility examples” appearing in US patents 8361514 and 8389005 (Gojón Romanillos 2013a, b); the most comprehensive claim in the latter patent (Claim 24) covers “a method of treating cancer, hypercholesterolemia, cardiovascular disease or Down Syndrome, said method comprising providing to a subject in need thereof a therapeutically effective amount of an active sulfur compound selected from the group consisting of H2S, sodium hydrogen sulfide, sodium sulfide, potassium sulfide, calcium sulfide, sodium hydrosulfide dihydrate, sodium sulfide nonahydrate, and ammonium sulfide”. The breadth of this claim is such that it stakes out for the sole inventor an enormous territory.
After his initial success — and prompted by it — Gojón Romanillos asked his father, Dr. Gabriel Gojón Zorrilla to join Nuevas Alternativas Naturales (as Head of R&D) in order to help in developing a prototype of an improved H2S donor capable of slow and sustained release of H2S (i.e. an H2S prodrug). They decided to contact Dr. David J. Lefer (a well-known expert in H2S signaling then at Emory University School of Medicine), flew to Atlanta and remained there until Gojón Romanillos convinced him to enter into a collaboration with them.
Under the terms of said collaboration they synthesized (in Nuevas Alternativas Naturales laboratory, Monterrey, Mexico) a long series of mostly novel sulfur-rich organic compounds such as trisulfides, Bunte salts, diacyl polysulfides, and compounds of the general formula RO-CO-S-S-CO-OR. However, all of these compounds proved unsatisfactory when assayed at Emory by Dr. Lefer and his team, since they were all unable to generate significant increases in blood H2S concentration when parenterally administered (i.e. injected) to mice —with diallyl trisulfide (DATS) used as a positive control.
At this point Gojón Romanillos and Gojón Zorrilla hypothesized that the most effective and least toxic H2S prodrug might prove to be one based on a supramolecularly modified allotrope of sulfur, since they knew — from the literature — that some eukaryotic cells (including erythrocytes) are capable of reducing elemental sulfur with concomitant sulfide generation. Gojón Zorrilla then embarked on a project aimed at preparing a highly bioavailable form of elemental sulfur essentially free from heavy metals and other undesirable impurities.
After numerous futile attempts, he discovered that highly subdivided elemental alpha-sulfur containing small amounts of coprecipitated sodium sulfate and traces of sodium thiosulfate and sodium polythionates could be obtained by reacting — at atmospheric pressure — a solution of sodium sulfide or hydrosulfide with an inorganic sulfite or bisulfite (also dissolved in water) and with a strong protic acid (Gojón Romanillos G. and Gojón Zorrilla G., 2014). When a chow formulated so as to contain a small percentage of this composition (code named SG1002) was fed to mice at Emory, SG1002 yielded blood and tissue H2S concentrations equal to or higher than those obtained by intraperitoneally injecting DATS (garlic-derived diallyl trisulfide).
Interestingly, several weeks after receiving the first sample of SG1002, Dr. Lefer was still reluctant to assay it in mice because the method being routinely used in his lab was applicable only to water-soluble samples. Since SG1002 solubility in water is nil, it was not possible to use a procedure which required injecting a predominantly aqueous solution. In fact, the solubility of SG1002 in DMSO, ethanol and other innocuous solvents is also almost nil. It proved quite difficult to persuade him to orally administer SG1002 to mice by a method other than gavage (forced feeding), as it has been shown that such method often distorts physiological responses.
SG1002 high bioactivity is related to several factors, including its small particle size and the fact that, unlike pure elemental sulfur, the surface of each particle is rendered partially hydrophilic by the small amounts of ionic species present. SG1002 may be categorized as an alpha-sulfur rich composite material of high reactivity and high oral bioavailability.
It is also extremely important to bear in mind that the properties (solubility in water, solubility in carbon disulfide, etc.) of this novel supramolecularly modified form of sulfur are quite different from those of elemental alpha-sulfur. SG1002 is both orally and parenterally active, its bioavailability is very high and independent of the levels of H2S-generating enzymes, it is able to release H2S in a slow and sustained manner, it is odorless, tasteless, and its shelf life is of the order of years. The researchers currently hypothesize that SG1002 is bioconverted into H2S in the gut by epithelial intestinal cells.
Between 2009 and 2010, Dr. Felipe Arturo Morales, MD, PhD, conducted — in Monterrey, Mexico — a randomized, double blind, placebo-controlled clinical trial in order to determine whether subjects suffering from oligoasthenozoospermia (a condition that leads to male subfertility) could benefit from treatment with orally administered SG1002. Dr. Morales is Director of the Reproductive Medicine Center at Hospital Universitario Dr. José E. González, Nuevo León Autonomous University (UANL), Monterrey, Mexico.
He was persuaded to carry out this study by Gojón Romanillos, who provided him with literature on the powerful direct and indirect antioxidant effects of H2S, as well as evidence supporting the hypothesis that oxidative stress is an important contributor to sperm dysfunction and male infertility.
Infertile men presenting with oligoasthenozoospermia treated with oral SG1002 (1,500 mg/day) had increased sperm concentration and motility and less morphologic abnormalities compared to those treated with placebo.
Also prompted by Gojón Romanillos, Dr. Alberto Siller, MD and certified pediatric oncologist, undertook a consecutive case series study involving eleven children aged 18 months and over and in two adults. These patients received between 1,200 mg and 3,600 mg SG1002 daily for conditions including osteosarcoma (n=2), hydrocephalus with or without tumor (n=6), medulloblastoma (n=1), squamous cell carcinoma (n=1), acute lymphoblastic leukemia (n=1), heart failure (n=1) and type II diabetes (n=1). No information on adverse effects was reported. In all cases the patient´s condition improved —in particular fatigue, inflammation, pain, headache, cardiac function and glycaemia improved, and tumors shrank or disappeared. These results are described in US Patent 8771755.
NOTE: The eleven children treated by Dr. Siller were terminal cancer patient’s refractory to chemotherapy and/or radiotherapy. The probability of observing spontaneous remission in the eleven consecutive cases is approximately 1 in 10000000000000000000000000000000000000000000000000000000, considering that the probability of observing spontaneous remission in an average cancer patient in any stage is estimated to be 1 in 1,000,000.
Once animal testing at Emory had provided evidence that SG1002 is hepatoprotective and effective in the prevention and treatment of ischemia-reperfusion injury, Gojón Zorrilla developed, validated and documented detailed methods for determining particle size distribution, percent elemental sulfur, percent sodium sulfate, percent residual solvents, etc., which were then shared with Dr. Lefer´s team; they confirmed the characterization results using powder X-ray diffraction and Fourier transform mass spectroscopy with static nanospray ionization (Kondo K. et al. 2013). Furthermore, the mass spectral results evidenced the presence of sodium tri-, tetra-, and pentathionates.
Gojón Romanillos and Gojón Zorrilla then (ca. 2012) went on to examine the effects of exogenous H2S therapy — mediated by SG1002 — in a murine model of pressure overload-induced heart failure. The results demonstrated that oral SG1002 therapy prevents the transition from compensated to decompensated heart failure, in part via upregulation of endothelial nitric oxide synthase and increased nitric oxide bioavailability (Kondo K. et al., 2013, “H2S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase”, Circulation, 127:1116-1127).
At this time (circa 2012) the collaboration´s outcomes included two publications: a review article (Predmore B.L. et al., 2012, “Hydrogen sulfide in biochemistry and medicine”, Antioxidants and Redox Signaling, 17(1):119-140) and the “Circulation” paper (see above); it is worth mentioning that the review article has accrued over 300 citations to this date. Additionally Gojón father and son travelled to Los Angeles in order to present a poster (Kondo K., Bhushan S., Condit M.E., King A.L., Predmore B.L., Wang R., Gojón G. (Sr), Gojón G. (Jr), Lefer D.J.; “H2S protects against pressure overload-induced hypertrophy and heart failure”) at the Scientific Sessions of the American Heart Association in 2013.
On February 20th, 2014, the Secretariat of the Third International Conference on Hydrogen Sulfide in Biology and Medicine (Kyoto, Japan, June 2014) informed Gojón Zorrilla, in writing, that “the following abstract you submitted has been accepted for oral presentation during the conference titled “Heart failure clinical trial to evaluate the safety of SG1002 —a novel hydrogen sulfide donor”.
On March 28th, 2014, the Conference Secretariat notified Gojón Zorrilla that “the program and the schedule of your presentation have been fixed as follows: Session 5, Therapeutics and Development of H2S-based drugs; June 5 (Thu), 10:15-10:30; Program Number S5-4; Title: ‘Phase I heart failure clinical trial to evaluate the safety of SG1002- a novel H2S donor’; presentation style: oral.”
In view of the aforementioned developments Gojón Romanillos and Gojón Zorrilla decided to found a pharmaceutical company: Sulfagenix Inc. was incorporated in Delaware and two more scientists joined the team: Drs. Anthony T. Giordano (the first Sulfagenix Chairman and CEO) and John Elrod.
Dr. Giordano and Gojón Zorrilla chose an Australian CRO (IDT-Australia) to carry out the preparation of the first multikilo lot of SG1002 under cGMP conditions. After only two exploratory small-scale runs aimed at familiarization of IDT personnel with the process developed, IDT was able to scale it up and obtain, on December 2013, a 6 kg lot of SG1002 that was within specifications previously set by Drs. Gojón and Giordano.
This seamless transfer of synthetic technology and analytical protocols from Nuevas Alternativas Naturales to IDT-Australia was enabled by frequent and fluid communication among the parties — NAN, IDT-AUS and Dr. Giordano — and by Gojón´s thorough and detailed process description at the 3 kg scale, as well as by an appreciation of the physicochemical principles involved.
Drug material (the expression “drug substance” is inadequate in this context since SG1002 is neither a substance nor a mixture, but a composite material) from this lot was used to fill capsules to be administered to participants in SG1002 phase I heart failure clinical trial (Gojón G. Sr., Gojón G. Jr. et al. 2014) which was carried out in Australia in 2014. Now deceased Dr. Henry Krum, an internationally-recognized heart failure researcher at Monash University (Melbourne), served as principal investigator, Dr. Giordano was in charge of coordinating all aspects of the trial, while Gojón Romanillos and Gojón Zorrilla helped drafting the clinical trial investigator brochure and provided advice (both conceptual and practical) on compounding, formulation, oral dosage form, etc.
In the double-blinded, placebo-controlled, dose-escalation study — which involved both healthy and heart failure subjects — doses of up to 800 mg twice daily for seven days were well tolerated with minimal side effects; Gojón father and son’s findings prove that SG1002 increases blood hydrogen sulfide and nitric oxide levels, and suggest that it attenuates increases in Brain Natriuretic Peptide (BNP) in heart failure patients (Polhemus D.J. et al., 2015).
After tolerability, lack of adverse effects and optimal oral dose of SG1002 were established in Australia, Sulfagenix stands ready to initiate a phase II clinical trial. Its main purpose will be to assess the safety of chronic oral administration of SG1002 to heart failure patients and to determine whether such administration results in improvements in H2S levels and clear demonstration of bioactivity as evidenced by a reduction in biomarkers of oxidative stress, inhibition of inflammatory biomarkers and activation of nitric oxide bioactivity. Secondary goals of the study are to determine if chronic oral treatment with SG1002 leads to cardiac remodeling and clinical benefits.
SG1002 physicochemical and therapeutic profiles match very closely those of the ideal H2S prodrug, since it optimizes immune function and is:
Safe, with a very high therapeutic index and very mild gastrointestinal side effects;
Orally active and slow H2S-releasing;
Odorless and tasteless (it may be sprinkled on food if patient has trouble swallowing a capsule or tablet);
Effective independently of H2S-generating enzyme levels;
Able to release H2S at a bioregulated, sustained and constant rate;
Indefinitely stable (shelf life greater than 2 years);
Versatile (it may be administered in a capsule or tablet);
Gastroprotective, enteroprotective, hepatoprotective, cardioprotective, renoprotective, neuroprotective, otoprotective, eye protective, chondroprotective, osteoprotective, pancreoprotective, and antifibrotic.
Today, the future of SG1002 looks brighter than ever: it has been mentioned in over 150 scientific papers and meeting abstracts, and the results of research involving it and carried out in different animal models by multiple research groups in USA, Europe, and Mexico have been highly encouraging.
Furthermore, overwhelming evidence (Gojón G. and Morales G.A., 2020) now supports the view that H2S donors will soon prove their therapeutic value in a large number of indications, including infections by enveloped viruses, diabetes, fibrotic diseases, pathologies derived from ischemia-reperfusion damage, hyperproliferative diseases (including cancer), neurodegenerative diseases, gastrointestinal pathologies, pre-eclampsia, arthritis, cardiovascular diseases, hepatic and renal diseases, autoimmune pathologies, systemic sclerosis, multiple sclerosis, Duchenne muscle dystrophy, allergies, osteoporosis, sarcopenia, hearing loss, lens opacification, testicular dysfunction, male subfertility, erectile dysfunction, periodontitis and aging. At least in the cardiometabolic and oncologic settings, current evidence supports the view that H2S-based treatments are often capable not only of achieving long-term functional recovery, but also of leading to reversal of damage to tissues and organs.
According to highly regarded experts (John L Wallace et al., 2018; Cao X et al., 2018), “SG1002 for cardiovascular disorders and ATB-346 for arthritis have progressed into clinical trials and have shown considerable promise (…) SG1002 produces more sustained and consistent levels of hydrogen sulfide in plasma (…) Sulfagenix has demonstrated that administration of SG1002 can restore to normal the plasma H2S and no levels in CHF patients, thereby reducing the severity of, or preventing, heart failure (…) Importantly, the levels of hydrogen sulfide in these subjects (i.e., the volunteers participating in the phase I clinical trial) remained below cytotoxic concentrations”. The authors conclude that “there is now some solid evidence that H2S-based therapeutics have considerable promise for a number of indications… Interestingly, a promising outcome has been observed for some pediatric cancer patients as described in patent US8771755.”
Therefore, we may confidently predict that the impact of SG1002 on global health and healthy longevity will be comparable to that of antibiotics.
Finally, Sulfagenix’s intellectual property around SG1002 is exceptionally strong and broadly protected by three issued US patents covering synthesis, composition of matter and method of use (US8361514, US8389005, US8771755), as well as by issued patents in Japan (JP5992525), Australia (AU2012321444), China (CN-ZL201280055643.5), Mexico (MX 360050) and Europe (EP2756757), including additional patent applications (Brazil, Canada).