Novel Treatments in the Pipeline for Neuropathic Pain

By Gail Schechter, Ph.D.
Novel Treatments in the Pipeline for Neuropathic Pain Characterized by sensations of burning, numbness, and tingling, neuropathic pain is debilitating and difficult to treat; it afflicts more than 5 million persons in the U.S., most patients are unsuccessfully treated, and the cost in lost productivity exceeds $100 billion annually.

Neuropathic pain has multiple etiologies, including metabolic disease, infectious disease, mechanical trauma, central nervous system disorders, toxic agents, compression injuries, and malignant conditions. Specific conditions commonly associated with neuropathic pain include: diabetes, postherpetic neuralgia (shingles), HIV/AIDS, cancer/chemotherapy, alcoholism, trigeminal neuralgia (tic douloreux), fibromyalgia, complex regional pain syndrome, phantom limb pain, carpal tunnel syndrome, back pain, multiple sclerosis, spinal cord injury, and stroke.

For most of the past 20 years, pharmacological treatment has depended primarily on a handful of medications, including old-fashioned tricyclic antidepressants, topical lidocaine and capsaicin patches, narcotics such as oxycontin, the painkiller tramadol, and the widely prescribed gabapentin (Neurontin), originally developed as an anti-seizure medication that modulates calcium influx and GABA transmission.

Big Pharma Provides Pain Relief
Pfizer has turned gabapentin into a $3 billion per year blockbuster medication (not without some bumps) and has recently launched its follow-on medication, pregabalin (Lyrica), fondly known as "super Neurontin." Studies indicate a superior therapeutic index for pregabalin compared to gabapentin. Launched in 2004 in Europe and the U.S., pregabalin was approved by the FDA to treat neuropathic pain associated with diabetic peripheral neuropathy and post-herpetic neuropathy, as well as adjunct treatment for partial seizures. In addition to the analgesic and anticonvulsant indications, it is likely that an anxiolytic indication will be approved in the near future.

Lilly's duloxetine (Cymbalta) also was launched in 2004. As a member of the new generation of antidepressants, duloxetine is a combined serotonin and norepinephrine reuptake inhibitor (SNRi). In addition to its approved indication for depression, it received an additional indication for pain management of neuropathic pain associated with diabetic peripheral neuropathy.

Emerging Therapeutic Targets for Neuropathic Pain
The recent BIO Emerging Company Investor Forum in San Francisco in October showcased more than 200 promising new companies, and it was clear that pain was a burning topic. Company presentations underscored major themes in current pain therapeutics, including: re-emergence of the N-methyl-D-aspartate (NMDA) receptor complex as a suspect of interest; NMDA receptor subtype-specific targets; increased understanding of physiological mechanisms of action; improved drug side effects profiles; better animal models to transition from preclinical to clinical studies; enhanced therapeutic index in humans; emphasis on oral formulations; and novel delivery techniques. Highlights from selected companies focused on pain, mainly neuropathic, illustrate the range of treatment candidates working their way through the pain pipeline.

New Tricks for Old Drugs
A resurgence of interest in NMDA receptors is evident in current pain research. New and improved versions of NMDA receptor antagonists, receptor subtype targets such as gycine, and ion channel modulators have been revived and refined.

Anavir Pharmaceuticals
Anavir focuses on the NMDA receptor as a prime target for the control of neuropathic pain. Excessive activation of the NMDA receptor has been implicated in many diseases, and pharmacological agents that attenuate NMDA receptor activity have been shown to be neuroprotective.

Anavir is developing Neurodex, dextromethorphan in combination with an enzyme inhibitor to block the rapid metabolism of dextromethorphan and maintain elevated blood levels. The rationale for using dextromethorphan to treat neuropathic pain is that it is a potent antagonist of the NMDA receptor. The use of low dose quindine sulfate, an established medication for cardiac arrhythmia, blocks enzyme activity responsible for the rapid degradation of dextromethorphan and sustains elevated blood levels thought to be effective in treating neurological disorders.

Neurodex currently is being tested for the indication of neuropathic pain. Avanir has completed a Phase II trial in patients with diabetic neuropathy. Treatment was well-tolerated and significantly decreased pain intensity. Avanir currently is discussing the Phase III protocol with FDA. Neurodex is also in Phase III clinical trials for uncontrolled laughter or tearfulness, called pseudobulbar affect, occurring in patients with amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, and stroke.

GB Therapeutics Ltd.
GB Therapeutics is targeting the NMDA glutamate receptor recognized for its role in pain and memory. The glutamate antagonist GT 3381 licensed from Chiesi showed good pain relief and a superior safety profile in humans.

Touted as the first new treatment in the third-generation oral NMDA modulators, GT 3381 currently is in Phase II clinical trials as a first-line therapy for neuropathic pain. The company also is developing GT 1061 as a neuroprotective agent to slow the progression of memory and cognitive deficits in Alzheimer's disease.

VistaGen Therapeutics, Inc.
VistaGen is developing a drug targeting epilepsy and neuropathic pain. VistaGen's lead drug candidate AV-101 is an NMDA receptor antagonist entering clinical development. This drug addresses the limitations of previous NMDA receptor antagonists by providing a high therapeutic index, i.e., potent efficacy and minimal adverse side effects. AV-101, L-4-chlorokynurenine, is a novel orally available prodrug (7-chlorokynurenic acid) that is preferentially converted to a potent glycine receptor antagonist at the site of neural damage, where it protects neurons from excitotoxic cell death. The company expects to initiate its AV-101 clinical program for epilepsy and neuropathic pain in early 2006.

The company's second drug candidate, AV-102, modulates neural pathways essential for memory and cognitive function and has therapeutic applications for mental decline associated with disorders of aging. The company also has a unique drug discovery program based on the use of clinically predictive in vitro embryonic stem cells to identify a new generation of drug candidates to treat central nervous system disorders.

Evotec Neurosciences GmbH
Evotec is developing an NMDA receptor NR2B subtype selective antagonist as a neuroprotective agent for neuropathic pain and central nervous system disorders including Parkinson's disease, Alzheimer's disease, stroke, and traumatic brain injury. Previous efforts to develop less selective NMDA antagonists have been plagued by a narrow therapeutic index and delicate balance between clinical benefits and side effects.

The NR2B receptor is forebrain specific and appears to have an improved side effect profile and wider therapeutic index. Its oral availability and lack of off-target responses show promise in animal models. As the company's lead compound, it is anticipated that it will enter into Phase I clinical trials in mid-2005.

Neuromed Technologies, Inc.
Neuromed is the only company in the world with a sole focus on developing calcium channel drugs. Using proprietary screening systems, Neuromed has identified a selective N-type calcium channel blocker with analgesic effects on severe chronic pain. Proof-of-principle for pursuing a peptide that blocks the N-type calcium channel is based on the drug ziconotide (Prialt) that effectively treats severe chronic pain but must be administered intrathecally (directly into the fluid surrounding the spinal cord through a surgically implanted catheter). Ziconotide, a synthetic equivalent of a naturally occurring conopeptide found in a marine snail known as Conus magus, selectively blocks calcium channels on the nerves that ordinarily transmit pain signals to the brain.

Of great importance is the oral and intravenous bioavailability of Neuromed's small molecule drug and its potential to deliver pain relief with minimal side effects. The company's lead candidate drug for chronic pain, NMED-160, is in a Phase I double-blind, randomized, placebo-controlled clinical trial designed to evaluate the drug's safety, tolerability, and pharmacokinetics in healthy individuals. Neuromed also has pipeline programs in anxiety, epilepsy, and cardiovascular disease.

International WEX Technologies, Inc.
Wex's lead product is Tectin for the initial indication of cancer pain and possibly other broad pain indications in the future. The sodium channel blocker, which acts to block pain signals, is derived from the pufferfish toxin, tetrodotoxin (TTX).

Phase II clinical trial results demonstrated that Tectin could relieve pain in refractory cancer pain patients. A recently initiated pivotal Phase IIb/III trial in 25 treatment centers is a randomized, placebo-controlled study in patients with moderate-to-severe cancer pain that is inadequately controlled by existing medication. Tectin is administered via intramuscular injection. The study results are expected in 2005.

ACADIA Pharmaceuticals
ACADIA is developing a class of small molecule agents that activate G-protein coupled receptors (GPCRs) implicated in pain. The two new receptor targets, NPFF and MrG, play a pharmacologically relevant role in pain signaling. The GCPRs appear to have potent, subtype-selective activity. The chemistries were initially found through ACADIA's chemical-genomics technology in which the company is systemically screening members of the GPCR family.

The new targets for pain expand the drug discovery efforts in pain therapeutics, including ACP-102 that targets a GPCR receptor and a preclinical development program targeting muscarinic receptors. The company is in clinical trials for ACP-103 and ACP-104 as adjunctive treatment of schizophrenia and Parkinson's disease.

Pain Therapeutics, Inc.
Pain Therapeutics is developing Oxytrex to treat severe chronic pain. Oxytrex is a unique oral painkiller that combines oxycodone plus ultra low-dose naltrexone to preferentially inhibit an excitatory effect of opioid receptors. This excitatory effect is believed to counteract analgesia and cause tolerance. Its inhibition enhances pain relief and minimizes opioid tolerance.

The company currently is conducting pivotal studies in patients with severe chronic low-back pain (first Phase III) and osteoarthritic pain (second Phase III) to compare the safety and efficacy of Oxytrex against the same total daily dose of oxycodone or placebo. Future research will be directed at the indication of neuropathic pain.

Pharmos
Pharmos' chemical library and list of lead preclinical drug candidates comprise two chemically distinct cannabinoid platforms, the dextrocannabinoid class of compounds and a separate class of cannabinoids showing selectivity toward CB2 receptor binding (PRS 375). Pharmos has completed preclinical/toxicological testing and is ready to move into clinical studies with PRS 375 for pain.

Currently, Pharmos is focusing its resources on its first neuroprotective product, dexanabinol, a non-psychotropic dextrocannabinoid currently undergoing Phase III clinical trials as a treatment for traumatic brain injury and Phase II testing as a preventative agent against post-surgical (CABG) cognitive impairment.

Dov Pharmaceuticals, Inc.
Dov's lead candidate is bicifadine, a chemically distinct molecule with a unique profile of pharmacological activity. It enhances and prolongs the actions of serotonin and norepinephrine by inhibiting the transport proteins that terminate their physiological actions, similar to the mechanism of action of duloxetine. Preclinical studies and clinical trials indicate that these actions may account for the analgesic properties of bicifadine in chronic pain conditions including neuropathic pain.

To date, bicifadine has been tested in 1,555 patients in a number of Phase I and II clinical trials using both immediate- and controlled-release formulations. Bicifadine demonstrated a statistically significant reduction in pain, in some cases comparable to or better than positive controls such as codeine. Phase III clinical trials are planned soon.

XenoPort, Inc.
XenoPort is focused on developing products that harness the body's intrinsic transport systems to improve the oral absorption, distribution, and pharmacokinetics of drugs. The company applies an integrated technology platform--consisting of transporter genomics, assay technology, and proprietary chemistries--to engineer drug molecules for active transport. XenoPort currently is applying its technology to off-patent drugs to provide new, patentable compounds with improved medicinal properties.

XenoPort is in the process of creating new patentable Transported Prodrugs. The company recently initiated two Phase II clinical trials with XB13512, XenoPort's proprietary experimental Transported Prodrug of gabapentin, as a potential treatment for post-herpetic neuralgia and restless legs syndrome.

AlgoRx
AlgoRx is focused on building a diversified portfolio of pharmaceutical products to treat pain. ALGRX 4975 is an injectable capsaicin product for localized, severe, intractable pain. A single administration is expected to provide analgesia for up to several months. Because ALGRX 4975 is injected directly into the painful tissue, it is anticipated to have much greater efficacy than low dose topical capsaicin that is currently available. Alternatively, during surgical procedures, it may be instilled into the surgical wound or onto the cut surfaces of skin, muscle, or bone. The company is pursuing multiple indications for ALGRX 4975: musculoskeletal pain (including osteoarthritis of the knee and tendonitis); post-surgical pain; and post-trauma neuropathic pain. ALGRX 4975 is currently in Phase II clinical development.

A second product in development is ALGRX 3268 (PowderJect(R) Dermal Lidocaine), a needle free, local dermal anesthetic providing analgesia within one minute. It is currently in Phase II clinical testing in children to reduce the pain associated with needlesticks for venipuncture or intravenous cannulations.

NeurogesX, Inc.
NeurogesX is taking a topical approach to treating neuropathic pain of peripheral origin. The company is developing a localized, high-concentration capsaicin dermal patch. The local anesthetic effect results from activation of the transient receptor potential vanilloid 1 (TRPV1) receptor (formerly vanilloid receptor 1 or VR1), a ligand-gated ion channel activated by agonists such as capsaicin. When capsaicin activates TRPV1, calcium enters the cell and pain signals are initiated. When TRPV1 is continuously activated through prolonged exposure to an agonist, excessive calcium enters the cell, initiating processes that result in long-term yet reversible impairment of nociceptor function. This is the proposed mechanism by which NGX-4010 delivers long-term relief to patients with neuropathic pain.

The lead candidate, NGX-4010, provides application of a pure, high-concentration form of synthetic capsaicin, known as trans-capsaicin, directly to the site of pain via a rapid-delivery dermal application system. This potential product is currently being studied in Phase III trials in postherpetic neuralgia and neuropathic pain related to HIV-associated neuropathy. Phase II trials are also ongoing for patients with neuropathic pain related to peripheral diabetic neuropathy.

Future Opportunities
Neuropathic and other chronic pain treatments still face formidable challenges. Increased efficacy, safety, onset of action, and continual day/night relief are desired, but as yet unattained, properties. It is likely that we will next see "me too" drugs following in the large footsteps of the anticonvulsants and antidepressants. The emerging compounds in the pipeline are innovative therapeutic candidates, but they still have a long way to go, and it is too early to predict their future.

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The author, Gail Schechter, Ph.D., president of BioIntelligence.com, a consulting company specializing in CNS technology assessment, product development, and grant writing, may be contacted at 415-921-8541 or at BioIntel@BioIntelligence.com.

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