Our goal is to develop a non-opiate, pen-injectable product that harnesses the proven activity of glucocorticoids to treat chronic pain, but improves the safety profile of these agents.

Hypothesis. Glucocorticoids act on several molecular targets in pain act at the nuclear level to modulate key genes involved in inflammatory processes. Our hypothesis is that by localizing dose to the intraneuronal environment, we minimize dose to the site of action in the neuronal cell body, limit systemic administration and thus limit systemic side effects. In other words, improve therapeutic index of glucocorticoids by localizing or “targeting” dose to the affected dermatome.

Inadequate treatment of pain is the single largest cost problem in the Veterans Administration and in the civilian population. Cost in the system to treat pain is driven largely by ineffective drugs, so that patients return to the physician repeatedly for re-evaluation and new combinations of various classes of drugs. In the civilian population pain is the most frequent reason that patients seek medical care, accounting for about 1.5% of all healthcare visits. (Taylor 2006) This is estimated to cost America about $100 billion in direct and $100 billion in indirect costs (Clark 2007).

The total cost of all treatment for Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF, in Afghanistan) returnees was estimated at $350 - $650 billion in 2007 (Clark 2007). Assuming 47% of OEF/OIF returnees seek treatment for pain, this suggests that the cost of treating their pain is $150 - $300 billion.

“... [I]t is expected that about 50% of all OIF/OEF servicemembers will eventually access VA healthcare”... of these, about half of OEF/OIF returnees (47%) will seek treatment for pain, and half of these will receive opiate therapy along with other, often CNS-active pain drugs. (Clark 2007)

Need to reduce opiates in pain care. There are many types of drugs prescribed to treat pain. Most of these agents including the anti-convulsants gabapentin (Neurontin®) and carbemazepine (Dilantin®, antidepressants, NMDA antagonists, opiates like Oxycontin®, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) like Celebrex® and capsaicin act on extracellular, usually single, molecular targets. However, the most effective but provide relief only to about 30%-50% of patients with chronic pain (Sindrup and Jensen 2000; Sindrup and Jensen 1999; Woolf and Mannion 1999; Baron 2000).

Of those being treated for pain, about 44% of injured troops receive some form of opiate therapy (Clark 2007). This level is consistent with historical use (Clark 2002). However, the effectiveness of opiates in treating the pain of our veterans is limited (Clark 2005) and may lead to reduced activity, cognitive impairment, increased depression (Clark 2005), and substance abuse. Over time, many patients taking opiate therapy fail to respond, requiring higher and higher doses to bring relief from pain. Tragically, opiates for pain may become the instrument of choice for suicide (Buckenmaier, remarks at ATACCC August 2008).

Rationale for glucocorticoids: history of high levels of effectiveness when localized. The effective use of injected glucocorticoids was first reported in 1925 (Viner 1925). Since then, injectable glucocorticoids have been used for many localized pain conditions. They are usually administered in-office as acute and adjunct therapy to oral therapy not only for pain, but also for endocrine and rheumatic disorders, collagen and dermatologic diseases, allergic states, ophthalmic diseases, leukemias and multiple sclerosis.

Localized forms of chronic pain like sciatica and leg and back pain are typically treated with a range of pain agents, where anti-inflammatory agents like celecoxib and ibuprofen are typically first-line therapy. However, selected studies show that when localized using invasive means eg epidural or intrathecal delivery, glucocorticoids can be 60% (McClain et al 2004) or 80% effective over a sustained period (two years) following a month of dosing (Kotani et al NEJM 2000).

How glucocorticoids work on pain. Chronic pain involves multiple molecular inflammatory mediators, with increasing evidence that complex changes occur in the expression profile of inflammatory and glial cells, particularly in the chronic phase. Glucocorticoids are potent inhibitors of pain because they act on many of the same mediators eg the pro-inflammatory cytokines IL-1β, IL-6 and IL-10 (Watkins et al 1995).

Glucocorticoids act by binding to the glucocorticoid receptor. The GC/GRx complex is translocated to the nucleus, where it binds to Glucocorticoid-Responsive Elements (GREs) on DNA and modulates transcription of many targets, including key pro-inflammatory cytokines such as IL-1β.

Using a fluorescent probe, we carried out other preliminary in vitro and in vivo studies that appear to confirm that the FA of the FA-NGF complex reaches the neuronal cell body after administration on the distal end of the neurons. We believe our findings above show that the glucocorticoid acts intraneuronally after absorption via NGF. The intraneuronal activity of FA is not only consistent with the established mechanism of glucocorticoids, it would also confirm recent reports that pain is modulated at the gene expression level (Mannes and Iadarola 2007; Yang et al 2007; Yang and Tao 2007; Pareek et al 2007; Yang et al 2006). These latter studies underscore recent work by Kawasaki et al who identified the role of matrix metalloproteases on IL-1β in the transition from acute to chronic pain (Kawasaki et al 2008). In other words, early administration of glucocorticoids – and downregulating the important IL-1β cytokine - during the acute phase may modulate the severity and occurrence of chronic pain.

Technology behind “targeted glucocorticoids: Nerve Growth Factor as targeting moiety minimizes and localizes dose. We modify glucocorticoids by linking them chemically to a protein which is present naturally in the nervous system, Nerve Growth Factor (NGF).

It has been established that sub-cutaneously (sub-c) administered NGF localizes to, and is absorbed by the neurons at the site of injection. The glucocorticoid-NGF conjugate will be given sub-c or intramuscularly (im) and absorbed by high-affinity receptors TrkA (gene family of tropomyosin-related kinases, or Trks). The TrkA receptors are expressed at the distal ends of sensory nerves near the site of injection, just under the skin, where the blood-nerve barrier is lacking and the receptors are exposed. The glucocorticoid-NGF conjugate is absorbed by TrkA receptors and moved via retrograde axonal transport to the neuronal cell body, or Dorsal Root Ganglia (DRG). Nerve Growth Factor thus targets and delivers drug to the intraneuronal site of action.

Distribution studies published by Genentech show that approx. 80% of NGF remains near the site of injection, creating a depot effect prior to degradation after about four days (Nguyen et al 2000; Nguyen et al 2001).

Genentech clinical studies of recombinant human NGF: safe and well-tolerated within dosing limits. In clinical studies carried out for Genentech of recombinant human NGF (rhNGF) in patients with HIV-associated sensory neuropathy, McArthur et al (2000) and Schifitto et al (2001) reported improvements in pain symptoms. These studies also showed dose-dependent, transient short-term pain at the injection site of rhNGF.

The first study used sub-c rhNGF in two cohorts of 0.1μg/kg and 0.3μg/kg plus sub-c placebo. Sub-c NGF at these dose levels was well tolerated. Fifty-one per cent of patients receiving the larger dose reported statistically significant relief from pain after about 12 weeks of treatment, suggesting that rhNGF had an analgesic effect as expected from preclinical studies. About 30% of patients reported non-dose limiting injection site pain; about 3% reported severe myalgia, possibly associated with overdosing. This biphasic clinical observation is consistent with subsequent studies that show that NGF appears to upregulate the anti-inflammatory cytokine IL-10.

Combining these observations with our preliminary studies exploring the effects of unbound NGF, we expect to remain within the established safety limits of NGF: we are not seeking a systemic effect. Our strategy is to increase the potency of the drug payload, thus minimizing the absolute requirement for targeting moiety.

Summary: case for Nerve Growth Factor as targeting moiety. In summary, our case that targeted glucocorticoids can be an effective and safe agent for treating localized, chronic pain takes into account the following observations: