Poster Number-28 - LX9211, a Novel Therapeutic Approach to Treatment of Neuropathic Pain

LX9211, a Novel Therapeutic Approach to Treatment of Neuropathic Pain

Purpose:

Neuropathic pain is a debilitating, chronic condition affecting millions of people. It is associated with several disease conditions including painful diabetic neuropathy (PDN) and post-herpetic neuralgia (PHN). The current standard of care (SOC) provides modest relief with less than half of the patients reporting ≥50% improvement.  Additionally, the current SOC is associated with undesirable side effects, including sedation and cognitive impairment.

We have identified and developed LX9211, an orally acting inhibitor of a novel target, adaptor-associated protein kinase 1 (AAK1), for the treatment of neuropathic pain. LX9211, taken once daily, demonstrated statistically significant reduction in average daily pain score (ADPS) compared to placebo in a Phase 2 clinical trial for PDN. Here, we present the mechanism of action (MOA) of this novel target and results from preclinical models of neuropathic pain. 

Methods:

Mice deficient in the AAK1 gene were tested for their response to neuropathic pain in the formalin model and spinal nerve ligation model. LX9211 was evaluated in a streptozotocin-induced PDN model in rats and a varicella-zoster virus (VZV) model of PHN in rats.

Mechanistic studies were conducted exploring the need for orally-administered AAK1 inhibitors to cross into the CNS tissue to achieve analgesic effect. The effect of AAK1 inhibitors on neural activity in pain-related circuits at spinal level were explored in a chronic constriction injury (CCI) model in the rat. Combination studies of AAK1 inhibitors with opioid antagonist (naloxone) and alpha-2 adrenergic antagonists (yohimbine and idazoxan) in preclinical models of neuropathic pain were conducted.

Results:

Mice deficient in the AAK1 gene were resistant to development of neuropathic pain. Oral administration of LX9211 led to robust reduction in pain in the preclinical models of PDN and PHN. The MOA required CNS distribution of the AAK1 inhibitor and resulted in reduced spontaneous firing in the dorsal horn neurons of the spinal cord. Importantly, the MOA does not involve the opioid pathway. It works via the alpha-2 adrenergic receptor pathway without directly modulating the alpha-2 adrenoreceptors.

Conclusion:

We have identified a novel target and an associated drug candidate for the treatment of neuropathic pain. The results from preclinical models have recently been bolstered by encouraging topline results from a Phase 2 clinical trial in patients who suffer with PDN and need better therapeutic options than those currently available.

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