Contrast media (CM) induced nephropathy (CIN) remains prevalent and debilitating, the third most common cause of acute renal failure. Based on more than 80 million (M) CM injections in the USA per annum, of which 10% take place in a population highly susceptible to the development of CIN, and a unit pricing of $200 per course, we estimate the total domestic potential market equals $1.6B. At present there is no meaningful competition for this market, either registered or in development. To meet this unmet medical need, Radikal Therapeutics is developing a first-in-class mitochondrial-selective K+-ATP channel opener that activates a major endogenous cytoprotective mechanism. In a rat model of CIN, R-801 administration reduced CM- induced elevation in serum creatinine by 85%, blocked the reduction in renal medullary blood flow, eliminated lipid peroxidation and peroxynitrite formation, abrogated activation of the nuclear cell death enzyme poly(ADP-ribose) polymerase, and reduced congestion and necrosis of the medullary ascending thick limb. R- 801 has also exhibited a safety profile consistent with its mitochondrial-selective pharmacology, as noted by the absence of the classic side-effects of sarcolemmal K+-ATP channel activation. Based on our striking efficacy and safety findings in rodents, we hypothesize that R-801 will demonstrate a favorable safety profile in FDA- mandated GLP toxicology and safety pharmacology studies in 2 species, a critical step in advancing our product towards clinical testing and FDA approval.
Specific Aim : Establish the acute safety, toxicity, and tolerance of IV CM in the minimum set of GLP toxicology and safety pharmacology studies required for FDA IND application. We will initially carry out an in-house process scale-up research and synthesis in order to generate a 4 kg batch size of R-801 required to support formal IND-enabling GLP studies and to serve as the basis for subsequent GMP manufacturing. We will then carry out the minimum set of required FDA-mandated IND- enabling GLP studies to support our intended application for a first-in-man, dose-escalation, single-dose investigation of IV CM in healthy human volunteers. Genetic toxicology studies will include: the Ames, chromosomal aberration, and mouse micronucleus assays. Safety pharmacology investigations will include: 1) rat neurobehavioral and respiratory studies, and 2) canine cardiovascular studies. IV dose range-finding and 2 week repeat-dose toxicology studies in rats and dogs, with associated toxicokinetic (TK) determinations, will serve to elucidate the NOAEL in each species, and provide the basis for the dose range to be explored for safety, tolerance, and pharmacokinetics in man. All of the above studies constitute the minimal safety battery required by the FDA to support an IND application. The introduction of R-801 into clinical development is expected to pioneer a new field of investigation (pharmacologic induction of IPC) and spearhead the scientific foundation for a novel treatment paradigm (selective mito-K+-ATP channel activation).
Radio contrast imaging is an invaluable and frequently used diagnostic modality, but its use is complicated by the subsequent development of kidney injury, often to the extent of requiring dialysis, particularly in populations at greatest risk, such as th elderly, diabetic, and those with preexisting renal impairment. There are no approved pharmaceutical therapies to prevent this complication. We are developing a novel prophylactic agent that protects the kidney from radio contrast administration by directly protecting kidney cells from injury. We now propose to undertake scale-up manufacturing of the candidate agent and to evaluate its safety profile in formal IND-enabling toxicology and safety pharmacology investigations.