KP544: A Drug to Treat Neurodegenerative Conditions including Alzheimer's Disease.

Introduction:
Nerve growth factor protein (NGF) has neuroprotective properties both in vitro and in vivo, and has been investigated as a treatment for peripheral neuropathy and Alzheimer’s disease. Because this large protein is difficult to administer, does not cross the blood-brain barrier, and is rapidly metabolized, it has not been clinically successful. As a novel alternative, KPI has discovered and is developing KP544, a small molecule that can be administered orally, enters the brain readily, and enhances the effects of endogenous NGF.

Clinical Studies:
Initial Phase I studies conducted in healthy male volunteers investigated a single 15mg dose of drug.  Blood levels of the drug were high and the half-life consistent with a once or twice a day dosing schedule.  No adverse effects were observed.  No statistically significant differences in the ventricular rates were observed between placebo and drug treated subjects. 

Preclinical Studies:

Pharmacokinetics
In rats, KP544 is at least 25% bioavailable when administered orally at 10 mg/kg. At two and eight hours after dosing, brain levels are 4 and 6 times higher than plasma levels. The plasma half-life is 0.6 hours in mice, 1.3 hours in rats and 3.0 hours in dogs. With a single oral dose of 1.3 mg/kg in a human volunteer, the plasma half-life was 3.9 hours and seventy percent of the drug was excreted unchanged in the urine within 24 hours.

Metabolism
In rats, a single major metabolite of KP544 detected in plasma was the cis-isomer of KP544 which had similar activity to KP544 in vitro. No metabolites were detected in the plasma of one human volunteer.

Neuroprotective Properties
KP544 is neuroprotective against glutamate and high dose staurosporine in vitro, and against quinolinic acid and taxol in vivo.

Efficacy in a Model of Cognition Deficits
In a rat model of neurodegeneration induced by intrastriatal injection of quinolinic acid, lesioned rats given daily oral doses of KP544 at 0.1 or 1.0 mg/kg/day were virtually indistinguishable from non-lesioned controls in cognition tests (radial arm water maze). At a dose of 0.02 mg/kg/day, there was a delay in the onset of action but the end result was the same as the higher doses. This degree of activity was unprecedented in this model. A significant reduction in lesion size (34%) was evident in treated rats at the higher doses. 

Efficacy against Peripheral Neuropathy
In a rat model of taxol-induced peripheral neuropathy, daily oral dosing with KP544 at 0.1 to 10 mg/kg/day ameliorated the taxol-induced reduction in caudal nerve conduction velocity.  There were no significant differences in efficacy between doses.

In vitro hERG Channel Assay
The acute in vitro effects of KP544 on hERG K⁺ channel current, recorded from stably transfected HEK-293 cells, were evaluated at nominal concentrations ranging from 30 nM up to 10 μM (limit of solubility). At a maximum achieved concentration of ~4.5 μM, KP544 was found to reduce hERG tail current to 46.30 ± 7.00% of its control value (equivalent to 53.70% block). A concentration-response curve was determined and the IC₅₀ value was calculated to be 3.63 μM.

Safety Studies
In a GLP-compliant 30-day oral toxicity study in rats and dogs funded by the NIH-National Institute on Aging, favorable results were obtained in eight studies including a cardiopulmonary safety pharmacology study in telemetered dogs and a battery of genotoxicity studies.  In rats, KP544 has a therapeutic index greater than 1000.

Mechanism of Action:
Nerve growth factor and cyclicAMP induce differentiation in neurons. KP544 enhances this differentiation in PC12 cells as measured by choline acetyltransferase levels. KP544 also enhances neurite outgrowth in PC12 cells, primary embryonic rat cortical neurons, and human neuroblastoma cells (SH-SY5Y). It blocks glutamate toxicity in primary cortical neurons. The site of action is below the MAP kinases in the differentiation signal cascade probably at the translational level. KPI has evidence that indicates the identity of the enzyme that is the molecular target of KP544.

Synthesis:
KP544 is produced by an efficient 5-step process using readily available and relatively inexpensive starting materials. This process can be readily scaled-up for commercial manufacture. More than two kilograms of GLP material were prepared by KPI for preclinical studies.

Patents:
Four patent applications covering novel compounds and their use in the treatment of various disorders of the nervous system have been filed. These applications have issued in the United States as USP 6,440,965, 6,583,148, 6,916,820 and 7,205,297. Applications corresponding to USP 7,205,297 which covers KP544 are pending in Europe, Canada and Japan.

Backup Compound:
KP546 is a structural analogue of KP544 with a similar efficacy profile to KP544 but with differing dose limiting toxicity.

Conclusions:
KP544 has a pharmacokinetic, safety, and efficacy profile consistent with clinical use. It is currently being developed for the treatment of mild cognitive impairment and Alzheimer's disease. It is also being considered as a new approach to neuroprotection during chemotherapy. KP544 has all the hallmarks of a 'breakthrough' drug in therapeutic areas where the unmet medical need is staggering.