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KP544: A Neuroprotective Agent

SUMMARY

KP544 is a small molecule substituted pyrimidine that binds to ATP-citrate lyase, amplifies the effect of endogenous NGF, and demonstrates neuroprotective activity.  The drug is administered orally, is readily absorbed and crosses the blood-brain barrier in therapeutically significant amounts. KP544 is currently in Phase I and is proposed for use in the treatment of age-related neurodegeneration and chemically induced peripheral neuropathy. A non-confidential data package is available upon request.

BACKGROUND

Nerve growth factor protein has been shown to have neuroprotective properties both in vitro and in vivo, and has been investigated as a treatment for 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. KPI’s search for an agent that would enhance the effects of endogenous nerve growth factor in nerve-like cells led to a series of substituted pyrimidines that were highly effective in amplifying the effects of nerve growth factor in vitro.  Subsequent animal studies led to the selection of KP544 for clinical development based on impressive neuroprotective effects.

TECHNOLOGY

Mechanism of Action
In vitro research into the mechanism of KP544 led to the conclusion that the site of action was somewhere below the MAP kinases in the signal transduction chain initiated by nerve growth factor. To further refine our mechanistic understanding, an affinity chromatography resin was prepared and tested to see what proteins bound to the drug.  Only one protein bound: ACL (ATP-citrate lyase).  ACL is a key enzyme in the synthesis of lipids.  It is a highly regulated enzyme that is phosphorylated and dephosphorylated.  In rat brains, this enzyme is preferentially localized in cholinergic nerve endings. 

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.  Over one kilogram of cGMP clinical trial material prepared by a former licensee is available for use in completing Phase I studies.

CLINICAL STUDIES

Initial Phase I studies in healthy male volunteers assessed the pharmacokinetics of the free base and salt forms of the drug. In the first part of the study, six fasted volunteers received single doses of 15 mg KP544 free base and 16.6 mg KP544 HCl with at least one week separation.  In the second part of the study, 18 volunteers received two of three treatments in the fed or fasted state: single doses of KP544 FB, KP544 HCl or placebo. Blood levels of the drug were high and a half-life of about four hours is consistent with a twice a day dosing schedule. Differences between the free base and salt forms were small. No significant adverse effects were observed.  No significant differences in the ventricular rates were observed between placebo and drug treated subjects.  

PRECLINICAL STUDIES

A comprehensive series of preclinical studies in rats and dogs demonstrated a good safety and pharmacokinetic profile with significant neuroprotective properties.

In Vitro Studies (Fyfe et al.)
KP544 has been shown to enhance the effects of endogenous nerve growth factor and cAMP that induce differentiation in neurons.  KP544 enhances neurite outgrowth in vitro with PC12 cells, primary embryonic rat cortical neurons, and human neuroblastoma cells (SH-SY5Y).  It blocks glutamate toxicity with primary cortical neurons.

Efficacy in a Model of Cognition Deficits (Krenitsky et al.)
In a rat model of neurodegeneration induced by intrastriatal injection of quinolinic acid, lesioned rats given daily oral doses of KP544 were virtually indistinguishable from non-lesioned controls in cognition tests (radial arm water maze). This degree of activity was unprecedented in this model. Moreover, a significant reduction in lesion size was evident in treated rats.

Efficacy against Chemo-Induced Peripheral Neuropathy (Arezzo et al.)
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

Efficacy in a Model for Huntington’s Disease
A pilot study conducted at Cambridge University assessed the effects of chronic dosing of KP544 on female transgenic R6/2 mice and their wild-type littermates.  Mice were fed 10 mg/kg KP544 in food pellets twice-a-day for 16 weeks.  Some weight loss and a significant increase in survival and in locomotor activity of treated mice were observed.  There were no obvious adverse side effects.  The positive results were confirmed in a study at Central Michigan University (Dey et al.)

Safety Studies
In a GLP-compliant 30-day oral toxicity study in rats and dogs funded by the National Institute on Aging, favorable results were obtained in all 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.

INTELLECTUAL PROPERTY

Patents
Four patents covering novel compounds and their use in the treatment of various disorders of the nervous system were granted in the United States. USP 7,205,297 covers KP544.

Approved IND’s
The following IND’s have been approved and are currently active:
IND#110628 for the treatment of chemo-induced peripheral neuropathy.
IND #112932 for the treatment of Alzheimer’s disease.

CONCLUSIONS

KP544 has a pharmacokinetic, safety, and efficacy profile consistent with its clinical use for the treatment of neurological disorders. While treatment of taxol-induced peripheral neuropathy is a promising indication, the drug also has potential for use in the treatment of neurodegenerative conditions such as mild cognitive impairment, Alzheimer’s disease and Huntington’s disease, alone or in combination with other therapeutic agents.  KP544 is a first-in-kind new drug breakthrough with a unique mechanism of action and huge potential in the treatment of neurological disorders.

SUPPORTING DOCUMENTS

The following non-confidential documents are available on request. All clinical and preclinical data are available in a confidential electronic database for efficient due diligence activities.

  1. Fyfe et al., “KP544 Amplifies the Effects of Nerve Growth Factor on Cell Differentiation and is Neuroprotective”, Krenitsky Pharmaceuticals, Drug Development Research 62:49-59 (2004).
  2. Krenitsky et al., “KP544, a Nerve Growth Factor Amplifier: Pharmacokinetics, Safety and Efficacy in the Rat”, Krenitsky Pharmaceuticals, Drug Development Research 62:60-70 (2004).
  3. Arezzo et al., “The Dose Effects of Compounds KP-0544 on Taxol-Induced Neuropathy in the Rat: Electrophysiologic Measures” (Albert Einstein College of Medicine, Mar. 27, 2002).
  4. Geist et al., “Wide Spectrum Modulation by KP-544 in Models Relevant for Neuronal Survival”, H. Lundbeck A/S, Neuroreport 18(6):571-575 (2007).
  5. Fujisawa Report, “Neurotrophic Actions of KP544 in vitro”.
  6. Phase I Poster “Pharmacokinetics of Free Base and HCl Forms of KP544/KRX-0501”.
  7. Neuroscience Poster 11-11-08 (Mechanism of Action).
  8. Cambridge Report, R6-2 Huntington’s.
  9. Dey et al., R6-2 Huntington’s.
  10. USP 7,205,297

 
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