KTX 0101 is the
sodium salt of the physiological
ketone, D-
beta-hydroxybutyrate (betaOHB). This
neuroprotectant, which has recently successfully completed clinical Phase IA evaluation, is being developed as an
intravenous infusion fluid to prevent the cognitive deficits caused by ischemic foci in the brain during
cardiopulmonary bypass (CPB) surgery. KTX 0101 maintains cellular viability under conditions of physiological stress by acting as a "superfuel" for efficient
ATP production in the brain and peripheral tissues. Unlike
glucose, this
ketone does not require phosphorylation before entering the TCA cycle, thereby sparing vital
ATP stores. Although no reliable models of CPB-induced
ischemia exist, KTX 0101 is powerfully cytoprotectant under the more severe ischemic conditions of global and focal
cerebral ischemia, cardiac
ischemia and lung
hemorrhage. Neuroprotection has been demonstrated by reductions in
infarct volume,
edema, markers of apoptosis and functional impairment. One significant difference between KTX 0101 and other potential
neuroprotectants in development is that betaOHB is a component of human metabolic physiology which exploits the body's own neuroprotective mechanisms. KTX 0101 also protects hippocampal organotypic cultures against early and delayed cell death in an in vitro model of
status epilepticus, indicating that acute KTX 0101 intervention in this condition could help prevent the development of epileptiform foci, a key mechanism in the etiology of
intractable epilepsy. In models of chronic
neurodegenerative disorders, KTX 0101 protects neurons against damage caused by dopaminergic
neurotoxins and by the fragment of
beta-amyloid,
Abeta(1-42), implying possible therapeutic applications for ketogenic strategies in treating Parkinson's and
Alzheimer's diseases. Major obstacles to the use of KTX 0101 for long term
therapy in chronic disorders, e.g., Parkinson's and
Alzheimer's diseases, are the
sodium loading problem and the need to administer it in relatively large amounts because of its rapid mitochondrial metabolism. These issues are being addressed by designing and synthesizing orally bioavailable multimers of betaOHB with improved pharmacokinetics.